[(Benzodioxan, benzofuran or benzopyran) alkylamino] alkyl substituted guanidines

ABSTRACT

The present invention is concerned with vasoconstricive [(benzodioxan, benzofuran or benzopyran)alkylamino]alkyl substituted guanidines having the formula ##STR1## the pharmaceutically acceptable acid addition salts thereof, and the stereochemically isomeric forms thereof, wherein X is O, CH 2  or a direct bond; R 1  is hydrogen or C 1-6  alkyl; R 2  is hydrogen, C 1-6  alkyl, C 3-6  alkenyl or C 3-6  alkynyl; R 3  is hydrogen or C 1-6  alkyl; or R 2  and R 3  may be taken together to form a bivalent radical of formula --(CH 2 ) m  --, wherein m is 4 or 5; or R 1  and R 2  taken together may form a bivalent radical of formula --CH═CH-- or of formula --(CH 2 ) n  --, wherein n is 2, 3 or 4; or R 3  may represent a bond when R 1  and R 2  taken together form a bivalent radical of formula --CH═CH--CH═, --CH═CH--N═, or --CH═N--CH═; R 4  is hydrogen or C 1-6  alkyl; Alk 1  is a bivalent C 1-3  alkanediyl radical; A is a bivalent radical of formula: ##STR2## wherein each R 5  is hydrogen or C 1-4  alkyl; wherein each R 6  is hydrogen or C 1-4  alkyl; Alk 2  is C 2-15  alkanediyl or C 5-7  cycloalkanediyl; and each p is 0, 1 or 2; provided that [2-[(2,3-dihydro-1,4-benzodioxin-2-yl)methyl]amino]ethyl guanidine is excluded. Pharmaceuticals which are useful as vaseconstrictors. Compositions comprising said guanidine derivatives as active ingredients, processes for preparing said guanidine derivatives and novel N-cyano guanidine, intermediates; and a use as a medicine are described.

This application is a division of application Ser. No. 08/256,995, filedJul. 29, 1994, now U.S. Pat. No. 5,541,180, which was based on PCTapplication Ser. No. PCT/EP 93/00435, filed Feb. 19, 1993, which claimspriority from U.S. patent application Ser. No. 07/842,560, filed Feb.27, 1992 now abandoned.

BACKGROUND OF THE INVENTION

In EP-0,387,771 there are described benzopyran derivatives which show aninhibitory activity on Maillard reaction and possess an antioxidizingeffect. In Arzneim.-Forsch. 25 (9), p. 1404 (1975) there is described[2-[(2,3-dihydro-1,4-benzodioxin-2-yl)methyl]-amino]ethylguanidine in astudy concerning noradrenaline depletion effects. In WO-83/03607 anumber of cyanoguanidines are described having anti-hypertensive andvasodilator activity. Our novel compounds differ in that they haveselective vasoconstrictor activity.

DESCRIPTION OF THE INVENTION

The present invention is concerned with [(benzodioxan, benzofuran orbenzopyran)alkylamino]alkyl substituted guanidines having the formula##STR3## the pharmaceutically acceptable acid addition salts thereof,and the stereochemically isomeric forms thereof, wherein

X is O, CH₂ or a direct bond;

R¹ is hydrogen or C₁₋₆ alkyl;

R² is hydrogen, C₁₋₆ alkyl, C₃₋₆ alkenyl or C₃₋₆ alkynyl;

R³ is hydrogen or C₁₋₆ alkyl; or

R² and R³ taken together form a bivalent radical of formula --(CH₂)_(m)-- wherein m is 4 or 5; or

R¹ and R² taken together form a bivalent radical of formula --CH═CH-- orof formula --(CH₂)_(n) --, wherein n is 2, 3 or 4; or

R³ may represent a bond when R¹ and R² taken together form a bivalentradical of formula --CH═CH--CH═, --CH═CH--N═, or --CH═N--CH═, whereinone or two hydrogen atoms can be replaced by halo, C₁₋₆ alkyl, C₁₋₆alkyloxy, cyano, amino, mono- or di(C₁₋₆ alkyl)amino, mono- or di(C₃₋₆cycloalkyl)amino, aminocarbonyl, C₁₋₆ alkyloxycarbonylamino, C₁₋₆alkylaminocarbonylamino;

R⁴ is hydrogen or C₁₋₆ alkyl;

Alk¹ is a bivalent C₁₋₃ alkanediyl radical;

A is a bivalent radical of formula: ##STR4## wherein each R⁵ is hydrogenor C₁₋₄ alkyl; wherein each R⁶ is hydrogen or C₁₋₄ alkyl;

Alk² is C₂₋₁₅ alkanediyl or C₅₋₇ cycloalkanediyl; and each p is 0, 1 or2; and

R⁷ and R⁸ each independently are hydrogen, halo, C₁₋₆ alkyl, C₃₋₆alkenyl, C₃₋₆ alkynyl, hydroxy, C₁₋₆ alkyloxy, cyano, aminoC₁₋₆ alkyl,carboxyl, C₁₋₆ alkyloxycarbonyl, nitro, amino, aminocarbonyl, C₁₋₆alkylcarbonylamino, or mono- or di(C₁₋₆ alkyl)amino; provided that[2-[(2,3-dihydro-1,4-benzodioxin-2-yl)methyl]amino]ethyl guanidine isexcluded.

The compounds of formula (I) wherein R², R³ or R⁶ are hydrogen may alsoexist in their tautomeric forms. Such forms although not explicitlyindicated in the above formula are intended to be included within thescope of the present invention.

As used in the foregoing definitions halo defines fluoro, chloro, bromoand iodo; C₁₋₄ alkyl defines straight and branch chained saturatedhydrocarbon radicals having 1 to 4 carbon atoms such as, for example,methyl, ethyl, propyl, butyl, 1-methylethyl, 2-methylpropyl and thelike; C₁₋₆ alkyl defines C₁₋₄ alkyl and the higher homologues thereofhaving 5 to 6 carbon atoms such as, for example, pentyl, hexyl,1-methylbutyl and the like; C₃₋₆ alkenyl defines straight and branchchained hydrocarbon radicals containing one double bond and having from3 to 6 carbon atoms, such as, for example, 2-propenyl, 3-butenyl,2-butenyl, 2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl and the like; andthe carbon atom of said C₃₋₆ alkenyl being connected to a nitrogen atompreferably is saturated, C₃₋₆ alkynyl defines straight and branchchained hydrocarbon radicals containing one triple bond and having from3 to 6 carbon atoms, such as, for example, 2-propynyl, 3-butynyl,2-butynyl, 2-pentynyl, 3-pentynyl, 3-hexynyl, and the like; and thecarbon atom of said C₃₋₆ alkynylradical being connected to a nitrogenatom preferably is saturated; C₃₋₆ cycloalkyl is generic to cyclopropyl,cyclobutyl, cyclopentyl and cyclohexyl; C₁₋₃ alkanediyl defines bivalentstraight and branch chained saturated hydrocarbon radicals having form 1to 3 carbon atoms, such as, for example, methanediyl, 1,2-ethanediyl,1,3-propanediyl, 1,2-propanediyl and the like; C₂₋₁₅ alkanediyl definesbivalent straight and branch chained saturated hydrocarbon radicalshaving from 2 to 15 carbon atoms such as, for example, 1,2-ethanediyl,1,3-propanediyl, 1,4-butanediyl, 1,5-pentanediyl, 1,6-hexanediyl,1,7-heptanediyl, 1,8-octanediyl, 1,9-nonanediyl, 1,10-decanediyl,1,11-undecanediyl, 1,12-dodecanediyl, 1,13-tridecanediyl,1,14-tetradecanediyl, 1,15-pentadecanediyl, and the branched isomersthereof; C₅₋₇ cycloalkanediyl defines bivalent cyclic saturatedhydrocarbon radicals such as, for example, 1,2-cyclopentanediyl,1,3-cyclopentanediyl, 1,2-cyclohexanediyl, 1,3-cyclohexanediyl,1,4-cyclohexanediyl, 1,2-cycloheptanediyl, 1,3-cycloheptanediyl,1,4-cycloheptanediyl.

The pharmaceutically acceptable acid addition salts as mentionedhereinabove are meant to comprise the therapeutically active non-toxicacid addition salt forms which the compounds of formula (I) are able toform. The latter can conveniently be obtained by treating the base formwith such appropriate acids as inorganic acids, for example, hydrohalicacids, e.g. hydrochloric, hydrobromic and the like; sulfuric acid;nitric acid; phosphoric acid and the like; or organic acids, forexample, acetic, propanoic, hydroxyacetic, 2-hydroxypropanoic,2-oxopropanoic, ethanedioic, propanedioic, butanedioic,(Z)-2-butenedioic, (E)-2-butenedioic, 2-hydroxybutanedioic,2,3-dihydroxybutanedioic, 2-hydroxy-1,2,3-propanetricarboxylic,methanesulfonic, ethanesulfonic, benzenesulfonic,4-methylbenzenesulfonic, cyclohexanesulfamic, 2-hydroxybenzoic,4-amino-2-hydroxybenzoic and the like acids. Conversely the salt formcan be converted by treatment with alkali into the free base form.

The term addition salt also comprises the hydrates and solvent additionforms which the compounds of formula (I) are able to form. Examples ofsuch forms are e.g. hydrates, alcoholates and the like.

The ##STR5## moiety may be acyclic in which case R¹ preferably ishydrogen, methyl or ethyl; R² preferably is hydrogen, methyl, ethyl,propyl or butyl; R³ preferably is hydrogen, methyl or ethyl. Said moietymay also be cyclic in which case it can represent radicals of formula:##STR6## wherein R³ in particular is hydrogen or methyl. The lattercyclic moieties may be unsubstituted or substituted, preferably withhalo, especially iodo; C₁₋₆ alkyl, especially methyl; C₁₋₆ alkyloxy,especially methoxy; cyano; amino; diC₁₋₆ alkylamino, especially,dimethylamino; or aminocarbonyl.

Interesting compounds are those compounds of formula (I), wherein Alk¹is --CH₂ --CH₂ -- or --CH₂ --, especially --CH₂ --.

Also interesting are those compounds of formula (I) wherein R⁴ ishydrogen or C₁₋₄ alkyl, especially methyl.

Further interesting compounds are those compounds of formula (I) whereinX is CH₂ and wherein R⁷ and R⁸ each independently are hydrogen; halo,preferably fluoro, chloro or bromo; C₁₋₆ alkyl, preferably methyl,ethyl, propyl or butyl; C₁₋₆ alkyloxy, preferably methoxy; hydroxy;cyano; amino; aminoC₁₋₆ alkyl, preferably aminomethyl; C₁₋₆alkylcarbonylamino, preferably methylcarbonylamino; or nitro.

Other interesting compounds are those compounds of formula (I) wherein Xis O and wherein R⁷ and R⁸ each independently are hydrogen; halo,preferably fluoro, chloro, bromo; C₁₋₆ alkyl, preferably methyl orethyl; C₁₋₆ alkyloxy, preferably methoxy; hydroxy, cyano or nitro.

Still other interesting compounds are those compounds wherein X is adirect bond and wherein R⁷ and R⁸ each independently are hydrogen, halo,preferably fluoro, chloro or bromo; or C₁₋₆ alkyl, preferably methyl orethyl.

Particular compounds are those compounds of formula (I) wherein Arepresents a radical of formula (a); Alk² is C₂₋₁₅ alkanediyl,especially C₂₋₁₀ alkanediyl, more in particular C2-6alkanediyl,preferably 1,3-propanediyl; R⁵ is hydrogen or methyl; and R⁶ is hydrogenor methyl.

Further particular compounds are those compounds of formula (I), whereinA represents a radical of formula (b) or (c), p is 0, 1 or 2, especially0 or 1, preferably 1; and wherein R⁵ and R⁶ each independently arehydrogen or methyl.

Particularly interesting are those compounds wherein the absoluteconfiguration of the the carbonatom at the 2-position in formula (I),indicated with an asterisk (*), is as shown in the formula hereunder.##STR7##

Particularly interesting compounds are those interesting or particularcompounds having substituents on the 7- or 8-position (as defined informula (I)) of the benzodioxan, benzofuran or benzopyran moiety.

Preferred compounds are those compounds of formula (I), wherein X isCH₂, R⁷ and R⁸ each independently are hydrogen, halo, C₁₋₄ alkyl, C₁₋₄alkyloxy, hydroxy or cyano, especially when substituted on the 7- or8-position of the benzopyran moiety, and wherein A represents a radicalof formula (a), wherein Alk² represents C₂₋₁₀ alkanediyl and R⁵ and R⁶each independently are hydrogen.

Most preferred compounds areN-[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]-N'-(1,4,5,6-tetrahydro-2-pyrimidinyl)-1,3-propanediamine,the stereochemical isomers thereof, particularly the R-isomer, and thepharmaceutically acceptable acid addition salts thereof.

The term "stereochemically isomeric forms" as used hereinbefore definesall the possible isomeric forms which the compounds of formula (I) maypossess. Unless otherwise mentioned or indicated, the chemicaldesignation of compounds denotes the mixture of all possiblestereochemically isomeric forms, said mixtures containing alldiastereomers and enantiomers of the basic molecular structure. More inparticular, stereogenic centers may have the R- or S-configuration;substituents on bivalent cyclic saturated hydrocarbon radicals may haveeither the cis- or trans-configuration and C₃₋₆ -alkenyl radicals mayhave the E- or Z-configuration. Stereochemically isomeric forms of thecompounds of formula (I) are obviously intended to be embraced withinthe scope of this invention.

The compounds of formula (I) can generally be prepared by reacting adiamine of formula (II) wherein A, R⁴, R⁷ and R⁸ are as defined underformula (I) with a reagent of formula (III) wherein R¹, R² and R³ aredefined under formula (I) and W₁ is a reactive leaving group such as,for example, halo, e.g. chloro, bromo; alkyloxy, e.g. methoxy, ethoxyand the like; aryloxy, e.g. phenoxy and the like; alkylthio, e.g.methylthio, ethylthio and the like; arylthio, e.g. benzenethio and thelike. ##STR8##

Said reaction can be performed by stirring the diamine of formula (II)with the reagent of formula (III) in an appropriate solvent such as, forexample, an alcohol, e.g. methanol, ethanol, propanol and the like; ahalogenated hydrocarbon, e.g. dichloromethane, trichloromethane and thelike or an ether. e.g. 1,1'-oxybisethane, 2,2'-oxybispropane,tetrahydrofuran, 1,4-dioxane and the like; an aromatic hydrocarbon, e.g.benzene, methylbenzene, dimethylbenzene and the like. Optionally a base,such as, for example, an alkalimetal carbonate, e.g. sodium or potassiumcarbonate; an alkalimetal hydrogen carbonate, e.g. sodium or potassiumhydrogen carbonate; an appropriate organic base, e.g.N,N-diethylethanamine, pyridine, N-(1-methylethyl)-2-propanamine and thelike bases, can be added to pick up the acid that may be formed duringthe course of the reaction. Elevated temperatures may enhance the rateof the reaction. Preferably the reaction is performed at the refluxtemperature of the reaction mixture.

The compounds of formula (I) can also generally be prepared by reductiveN-alkylation of an aminoderivative of formula (VI) with an appropriatealdehyde of formula (V), wherein r is 0, 1 or 2. ##STR9##

Said reaction is performed by stirring the reactants in an appropriatesolvent such as, for example, an alcohol, e.g. methanol, ethanol,propanol and the like; an ether, e.g. 1,1'-oxybisethane,tetrahydrofuran, 1,4-dioxane and the like; an aromatic solvent, e.g.benzene, methylbenzene, dimethylbenzene and the like. Optionally a waterseparator can be used to remove the water that is formed during thecourse of the reaction. The resulting imine can then be reduced bycatalytic hydrogenation on an appropriate catalyst, such as, for examplepalladium on charcoal, palladium on bariumsulfate, platinum on charcoal,Raney-Nickel and the like in a suitable solvent, such as, for example analcohol, e.g. methanol, ethanol and the like; an ether, e.g.tetrahydrofuran, 1,4-dioxane and the like; a carboxylic ester, e.g.ethyl acetate, butyl acetate and the like; or a carboxylic acid, e.g.acetic acid, propanoic acid and the like. Optionally the reaction may beperformed at elevated temperatures and/or pressures.

The intermediate aldehyde of formula (V) can, be formed by reducing anacyl derivative of formula (IV) wherein r is defined as above and Y ishalo, e.g. chloro, bromo. The acyl halide can be formed by reacting theacid of formula (IV) wherein Y=OH, with a halogenating reagent such asthionylchloride, phosphorus trichloride, phosphorus tribromide,oxalylchloride and the like. The latter reaction may be performed in anexcess of the halogenating reagent or in appropriate solvents such asfor example halogenated hydrocarbons, e.g. dichloromethane,trichloromethane and the like; aromatic hydrocarbons, e.g. benzene,methylbenzene, dimethylbenzene and the like; ethers, e.g.1,1'-oxybisethane, tetrahydrofuran, 1,4-dioxane and the like, or dipolaraprotic solvents, e.g. N,N-dimethylformamide, N,N-dimethylacetamide andthe like. Stirring and elevated temperatures may be appropriate toenhance the rate of the reaction. Said reduction of the acylhalide offormula (IV) can for instance be perforated by catalytic hydrogenationwith a catalyst such as palladium on charcoal, palladium onbariumsulfate, platinum on charcoal and the like in appropriate solventssuch as, for example ethers, e.g. 1,1'-oxybisethane, tetrahydrofuran,1,4-dioxane and the like; preferably in admixture of a dipolar aproticsolvent, such as, for example N,N-dimethylformamide,N,N-dimethylacetamide and the like. Optionally a catalyst poison can beadded, such as thiophene, quinoline-sulfur and the like. Thereactionsequence starting from the intermediate aldehyde of formula (IV)and yielding compounds of formula (I) may be performed as a one-potreaction.

The compounds of formula (I) can also be prepared by N-alkylating anamine of formula (VI) with an intermediate of formula (VII), wherein W₂is a reactive leaving group such as, for example, halo, e.g. chloro,bromo or iodo; sulfonyloxy, e.g. methanesulfonyloxy, benzenesulfonyloxy,methylbenzenesulfonyloxy and the like, in appropriate solvents such asketones, e.g. 2-propanone, 2-butanone and the like; ethers, e.g.1,1'oxybisethane, tetrahydrofuran, 1,4-dioxane and the like; aromatichydrocarbons, e.g. benzene, methylbenzene and the like; dipolar aproticsolvents, e.g. N,N-dimethylformamide, N,N-dimethylacetamide,dimethylsulfoxide and the like. ##STR10##

Stirring and heating may enhance the reaction rate. Optionally asuitable base may be added to pick up the acid that is formed during thecourse of the reaction, such as, for example an alkali metal carbonate,e.g. sodium carbonate, potassium carbonate; an alkali metal hydrogencarbonate, e.g. sodium hydrogen carbonate, potassium hydrogen carbonateand the like; an appropriate organic base, e.g. N,N-diethylethanamine,pyridine and the like.

The compounds of formula (I), wherein A is a bivalent radical of formula(a) and R⁵ is hydrogen, said compounds being represented by formula(I-a), may be prepared by debenzylation of an intermediate of formula(VIII). ##STR11##

Said debenzylation can be performed following art-known procedures suchas catalytic hydrogenation using appropriate catalysts, e.g. platinum oncharcoal, palladium on charcoal, in appropriate solvents such asalcohols, e.g. methanol, ethanol, 2-propanol and the like: ethers e.g.1,1'-oxybisethane, tetrahydrofuran, 2,2'-oxybispropane and the like.Optionally elevated temperatures and pressures may be applied.

The compounds of formula (I) wherein R¹ is hydrogen, said compoundsbeing represented by formula (I-b), can be prepared by hydrolysis of theintermediate cyanoguanidines represented by formula (IX-a). ##STR12##

Said hydrolysis can be performed by stirring the intermediatecyanoguanidine of formula (IX-a) in the presence of an acid such as, forexample a mineral acid, e.g. hydrochloric acid, hydrobromic acid,sulfuric acid and the like or an organic acid, e.g. acetic acid, formicacid and the like, optionally in admixture with an appropriate solventsuch as, for example, an alcohol, e.g methanol, ethanol, propanol andthe like; an ether, e.g. 1,1'-oxybisethane, 2,2'-oxybispropane,tetrahydrofuran, 1,4-dioxane and the like. In the course of thishydrolysis the intermediate (IX-b) can be formed. Said intermediate offormula (IX-b) can sometimes be isolated, and further hydrolyzedyielding compounds of formula (I).

The compounds of formula (I), can also be converted into each other byfunctional group transformations.

For instance the compounds of formula (I), wherein the ##STR13## moietyrepresents a pyrimidinyl moiety, said compounds being represented byformula(I-c), can be converted into the tctrahydroanalogs (I-d)following art-known catalytic hydrogenation procedures. ##STR14##

This reduction can be performed simultaneously with the debenzylationmentioned hereinabove in describing the synthesis of the compounds offormula (I-a).

Furthermore, compounds of formula (I) bearing a C₃₋₆ alkynylgroup orC₃₋₆ alkenylgroup can be converted into the corresponding compoundsbearing C₁₋₆ alkylgroup following art-known hydrogenation techniques.Compounds of formula (I) bearing a cyanogroup can be converted into thecorresponding compounds bearing an aminomethyl substituent followingart-known hydrogenation techniques. Compounds bearing an alkyloxysubstituent can be converted into compounds bearing a hydroxygroup bytreating the alkyloxy compound with an appropriate acidic reagent suchas for example, hydrohalic acid, e.g. hydrobromic acid orborontribromide and the like. Compounds bearing an amino substituent canbe N-acylated or N-alkylated following art-known N-acylation orN-alkylation procedures.

A number of intermediates and starting materials in the foregoingpreparations are known compounds which may be prepared according toart-known methodologies of preparing said or similar compounds and someintermediates are new. A number of preparation methods will be describedhereinafter in more detail.

The intermediates of formula (II) wherein A is a radical of formula (a)and R⁶ is hydrogen, said intermediates being represented by formula(II-a), can be prepared by reducing a nitrile of the formula (X) whereinq is 1 to 14, using art-known reduction conditions. Said reduction can,for instance, be performed by catalytic hydrogenation using anappropriate catalyst, such as, for example, Raney nickel, palladium oncharcoal, palladium on bariumsulfate and the like, in an appropriatesolvent, such as, for example, an alcohol, e.g. methanol, ethanol,propanol and the like; an ether, e.g. 2,2'-oxybispropane,tetrahydrofuran, 1,4-dioxane and the like, or a mixture of suchsolvents.

Preferably the reduction is conducted in the presence of ammonia.Optionally higher temperatures or pressures can be applied. ##STR15##

Said reduction can also be carried out by stirring the nitrile with areducing reagent, such as, for example, borane, lithium aluminumhydride, and the like, in an appropriate solvent, such as an ether, e.g.2,2'-oxybispropane, tetrahydrofuran, 1,4-dioxane and the like; or ahydrocarbon, e.g. pentane, hexane and the like; an aromatic solvent,e.g. benzene, methylbenzene, dimethylbenzene and the like. Optionallyelevated temperatures can be applied to enhance the reaction rate.

The intermediates of formula (X) can be prepared by reacting an amine offormula (XI) with a reagent of formula (XII), wherein W₂ and q aredefined as hereinabove, in an appropriate solvent such as, for example,a dipolar aprotic solvent, e.g. N,N-dimethylformamide,dimethylsulfoxide, acetonitrile and the like, an aromatic solvent, e.g.benzene, methylbenzene, dimethylbenzene and the like; a ketone, e.g.2-propanone, 4-methyl-2-pentanone and the like; an ether, e.g.1,1'-oxybisethane, tetrahydrofuran, 1,4-dioxane and the like. ##STR16##

A base as mentioned in the preparation of compounds of formula (I) fromintermediates of formula (II) and (III) may be added to pick up the acidthat is formed during the course of the reaction. Stirring arid elevatedtemperatures may enhance the reaction rate. In the formula of theintermediate amine (XI) R⁵ may also have the meaning of benzyl. Thisprotective group can then be removed in a later stage of the synthesis.

For the preparation of intermediates of formula (X) wherein q=2, saidintermediates being represented by formula (X-a) an interestingalternative for the above alkylation comprises stirring the amine offormula (XI) with 2-propenenitrile in an appropriate solvent such as forexample, an alcohol, e.g. methanol, ethanol, propanol and the like, anether, e.g. 1,1'-oxybisethane, tetrahydrofuran, 1,4-dioxan and the like.##STR17##

Elevated temperatures may be appropriate to enhance the rate of thereaction. Preferably the reactants are stirred at the reflux temperatureof the reaction mixture.

The intermediates of formula (IX-a), wherein R⁴, R⁷, R⁸, X, Alk¹ are asdefined hereinabove and A is a bivalent radical of formula (a), (c),(d), (e); and wherein R² is hydrogen, C₁₋₆ alkyl, C₃₋₆ alkenyl, or C₃₋₆alkynyl, and R³ is hydrogen or C₁₋₆ alkyl, or R² and R³ taken togetherform a bivalent radical of formula --(CH₂)_(m) --, wherein m is 4 or 5,are deemed novel.

The intermediates of formula (IX-a) can be prepared by reacting anintermediate of formula (II) with a reagent of formula (XIII), whereinW₁ is a reactive leaving group as defined under formula (III), ##STR18##Said reaction can be perforated by stirring the reactants in anappropriate solvent such as an alcohol, e.g. methanol, ethanol and thelike, an halogenated hydrocarbon, e.g. dichloromethane, trichloromethaneand the like, an aromatic solvent, e.g. benzene, methylbenzene,dimethylbenzene and the like, a dipolar aprotic solvent, e.g.N,N-dimethylformamide, N,N-dimethylacetamide and the like. Optionally abase as mentioned under the preparation of the compounds of formula (I)from intermediates of formula (II) and (III) can be added to pick up theacid that is formed during the course of the reaction. Preferably thereaction is performed at room temperature.

The intermediates of formula (XIII) can be prepared by reacting acyanamide of formula (XIV) wherein W₁ is defined as under formula (III),with an amine of formula (XV). ##STR19##

Said reaction can be performed by stirring the reactants in areaction-inert solvent such as, for example, a halogenated hydrocarbon,e.g. dichloromethane, trichloromethane and the like, an aromaticsolvent, e.g. benzene, methylbenzene and the like, an ether, e.g.1,1'-oxybisethane, tetrahydrofuran, 1,4-dioxane and the like. Optionallya base can be added to pick up the acid that is formed in the course ofthe reaction. Appropriate bases are alkali metal or earth alkaline metalcarbonates or hydrogen carbonates, e.g. sodium carbonate, sodiumhydrogen carbonate, potassium carbonate and the like. Elevatedtemperatures may enhance the reaction rate.

Pure stereochemically isomeric forms of the compounds of this inventionmay be obtained by the application of art-known procedures.Diastereoisomers may be separated by physical separation methods such asselective crystallization and chromatographic techniques, e.g. liquidchromatography. Enantiomers may be separated from each other by theselective crystallization of their diastereomeric salts with opticallyactive acids. Said pure stereochemically isomeric forms may also bederived from the corresponding pure stereochemically isomeric forms ofthe appropriate starting materials, provided that the reaction occursstereospecifically. Preferably if a specific stereoisomer is desired,said compound will be synthesized by stereospecific methods ofpreparation. These methods will advantageously employ enantiomericallypure starting materials. Stereochemically isomeric forms of thecompounds of formula (I) are obviously intended to be included withinthe scope of the invention.

The compounds of formula (I), the pharmaceutically acceptableacid-addition salts and stereochemically isomeric forms thereof haveinteresting pharmacological properties: they show 5HT_(1-like) agonisticactivity. The compounds of the present invention have potent andselective vasoconstrictor activity. They are useful to treat conditionswhich are related to vasodilatation. For instance, they are useful inthe treatment of conditions characterized by or associated with cephalicpain, e.g. migraine, cluster headache and headache associated withvascular disorders. These compounds are also useful in the treatment ofvenous insufficiency and in the treatment of conditions associated withhypotension.

The vasoconstrictor activity of the compounds of formula (I) can bedetermined using an in vitro-test as is described in "Instantaneouschanges of alpha-adrenoreceptor affinity caused by moderate cooling incanine cutaneous veins" in the American Journal of Physiology 234(4),H330-H337, 1978; or in the test described in the pharmacologicalexample, wherein the serotonin-like response of the compounds of thepresent invention was tested on the basilar arteries of pigs. Novelintermediates of formula (IX-a) as defined hereinabove show similarpharmacological activity.

In view of their useful pharmacological properties, the subjectcompounds may be formulated into various pharmaceutical forms foradministration purposes. To prepare the pharmaceutical compositions ofthis invention, an effective amount of a particular compound, in base oracid addition salt form, as the active ingredient is combined inintimate admixture with a pharmaceutically acceptable carrier, whichcarrier may take a wide variety of forms depending on the form ofpreparation desired for administration. These pharmaceuticalcompositions are desirably in unitary dosage form suitable, preferably,for administration orally, rectally, percutaneously, or by parenteralinjection. For example, in preparing the compositions in oral dosageform, any of the usual pharmaceutical media may be employed, such as,for example, water, glycols, oils, alcohols and the like in the case oforal liquid preparations such as suspensions, syrups, elixirs andsolutions: or solid carriers such as starches, sugars, kaolin,lubricants, binders, disintegrating agents and the like in the case ofpowders, pills, capsules and tablets. Because of their ease inadministration, tablets and capsules represent the most advantageousoral dosage unit form, in which case solid pharmaceutical carriers areobviously employed. For parenteral compositions, the carrier willusually comprise sterile water, at least in large part, though otheringredients, to aid solubility for example, may be included. Injectablesolutions, for example, may be prepared in which the carrier comprisessaline solution, glucose solution or a mixture of saline and glucosesolution. Injectable suspensions may also be prepared in which caseappropriate liquid carriers, suspending agents and the like may beemployed. In the compositions suitable for percutaneous administration,the carrier optionally comprises a penetration enhancing agent and/or asuitable wetting agent, optionally combined with suitable additives ofany nature in minor proportions, which additives do not cause asignificant deleterious effect to the skin. Said additives mayfacilitate the administration to the skin and/or may be helpful forpreparing the desired compositions. These compositions may beadministered in various ways, e.g., as a transdermal patch, as aspot-on, as an ointment. It is especially advantageous to formulate theaforementioned pharmaceutical compositions in dosage unit form for easeof administration and uniformity of dosage. Dosage unit form as used inthe specification and claims herein refers to physically discrete unitssuitable as unitary dosages, each unit containing a predeterminedquantity of active ingredient calculated to produce the desiredtherapeutic effect in association with the required pharmaceuticalcarrier. Examples of such dosage unit forms are tablets (includingscored or coated tablets), capsules, pills, powder packets, wafers,injectable solutions or suspensions, teaspoonfuls, tablespoonfuls andthe like, and segregated multiples thereof.

The compounds of the present invention therefore may be used asmedicines in conditions related to vasodilatation, more in particularhypotension, venous insufficiency and especially cephalic pain amongwhich migraine. The compounds of the present invention also provide amethod of treating warm-blooded animals suffering from conditionsrelated to vasodilatation, such as, hypotension, venous insufficiencyand especially cephalic pain among which migraine by administering aneffective amount of a compound of formula (I), a pharmaceuticallyacceptable acid addition salt or a stereoisomeric form thereof. Thoseskilled in the art could easily determine the effective amount from thetest results presented hereinafter. In general it is contemplated thatan effective amount would be from 1 μg/kg to 1 mg/kg body weight, and inparticular from 2 μg/kg to 200 μg/kg body weight. It may be appropriateto administer the required dose as two, three, four or more sub-doses atappropriate intervals throughout the day. Said sub-doses may beformulated as unit dosage forms, for example, containing 0.005 to 20 mg,and in particular 0.1 mg to 10 mg of active ingredient per unit dosageform.

The following examples are intended to illustrate and not to limit thescope of the present invention in all its aspects.

EXPERIMENTAL PART A. Preparation of the Intermediates EXAMPLE 1

a) To a stirred and cooled (0° C.) solution of 32.8 g of3,4-dihydro-2H-1-benzopyran-2-methanol in 71 ml of pyridine and 135 mlof benzene was added dropwise a solution of 41.9 g of4-methyl-benzenesulfonyl chloride in 72.5 ml of benzene. Uponcompletion, stirring was continued for 25 hours. The reaction mixturewas washed successively with a hydrochloric acid solution (10%), withwater and with a sodium carbonate solution (10%). The organic layer wasdried, filtered and evaporated. The residue was purified by columnchromatography (silica gel; CHCl₃ 100%). The eluent of the desiredfraction was evaporated, yielding 28.3 g of3,4-dihydro-2H-1-benzopyran-2-methanol 4-methylbenzenesulfonate (ester)as a solid residue, mp. 59.4° C. (interm. 1). In a similar way there wasalso prepared: 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol4-methylbenzenesulfonate (ester) (interm. 2).

b) A mixture of 7.7 g of intermediate (1), 5.3 g of benzenemethanamine,5 g of sodium carbonate and 250 ml of 4-methyl-2-pentanone was stirredand refluxed for 48 hours using a water-separator. The reaction mixturewas cooled and washed with water. The organic phase was dried, filteredand evaporated. The residue was purified by column chromatography(silica gel; CHCl₃ /CH₃ OH 90:10). The eluent of the desired fractionwas evaporated and the residue was converted into the ethanedioate saltin ethanol. The salt was filtered off and suspended in 2-propanone. Theproduct was filtered off and dried, yielding 1.16 g (19.5%) of3,4-dihydro-N-(phenylmethyl)-2H-1-benzopyran-2methanamine ethanedioate(1:1)(interm. 3).

In a similar way there was also prepared:

2,3-dihydro-N-(phenylmethyl)-1,4-benzodioxine-2-methanamine (interm. 4).

EXAMPLE 2

In EP-0.145.067 the synthesis of(+)-6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid (interm. 5)is described.

a) To a stirred and heated (±80° C.) mixture of 49.05 g of intermediate(5) and 244 ml of methylbenzene were added dropwise 54 ml of thionylchloride during a period of 85 minutes. Upon complete addition, stirringwas continued for 2 hours at 80° C. After cooling to room temperature,the reaction mixture was evaporated. The residue was taken up inmethylbenzene and the solvent was evaporated again, yielding 60.4 g(100%) of (+)-(S)-6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carbonylchloride as a residue (interm. 6).

b) A mixture of 46.9 g of intermediate (6) in 60 ml ofN,N-dimethylacetamide and 350 ml of 2,2'-oxybispropane was hydrogenatedin the presence of 3 g of palladium-oncharcoal catalyst (10%) and 5 mlof a solution of thiophene in methanol (4%). After the calculated amountof hydrogen was taken up, the catalyst was filtered off and the filtratewas added to a mixture of 25 g of benzenemethanamine, 20 g of potassiumacetate and 300 ml of methanol. This mixture was hydrogenated again inthe presence of 3 g of palladium-on-charcoal catalyst (10%) and 3 ml ofa solution of thiophene in methanol (4%). After the calculated amount ofhydrogen was taken up, the catalyst was filtered off and the filtratewas evaporated. The residue was poured into water and the whole wasbasified with NaOH (50%). The product was extracted with dichloromethaneand the extract was dried, filtered and evaporated. The residue waspurified by column chromatography (silica gel; CH₂ Cl₂ /CH₃ OH 95:5).The eluent of the desired fraction was evaporated and the residue wasconverted into the hydrochloride salt in 2-propanone by adding2-propanol saturated with HCl. The salt was filtered off and dried,yielding 46.9 g (69.3%) of(+)-(S)-6-fluoro-3,4-dihydro-N-(phenylmethyl)-2H-1-benzopyran-2-methanaminehydrochloride; mp. 210.7° C.; [α]_(D) ²⁰ =+92.63° (conc.=0.1% in CH₃ OH)(interm. 7).

In a similar way there were also prepared:

(S)-3,4-dihydro-N-(phenylmethyl)-2H-1-benzopyran-2-methanamine (interm.8);

(-)-(R)-6-fluoro-3,4-dihydro-N-(phenylmethyl)-2H-1-benzopyran-2-methanaminehydrochloride; mp. 210.4° C.; [α]_(D) ²⁰ =-79.47° (conc.=0.1% in CH₃ OH)(interm. 9);

(R)-3,4-dihydro-N-(phenylmethyl)-2H-1-benzopyran-2-methanamine (interm.10); and

(±)-3,4-dihydro-2-methyl-N-(phenyhnethyl)-2H-1-benzopyrano2-methanamine(interm 11).

c) A mixture of 28 g of intermediate (10) and 300 ml of methanol washydrogenated in the presence of 2 g of palladium-on-charcoal catalyst(10%). After the calculated amount of hydrogen was taken up, thecatalyst was filtered off and the filtrate was evaporated, yielding 18.2g (100%) of (-)-(R)-3,4-dihydro-2H-1-benzopyran-2-methanamine as cruderesidue (interm. 12).

In a similar way there were also prepared:

(±)-2,3-dihydro-1,4-benzodioxine-2-methanamine (interm. 13);

(S)-3,4-dihydro-2H-1-benzopyran-2-methanamine (interm. 14);

(±)-6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanamine (interm. 15);

(±)-3,4-dihydro-6-methoxy-2H-1-benzopyran-2-methanamine (interm. 16);and

(±)-3,4-dihydro-2H-1-benzopyran-2-methanamine (interm. 17).

EXAMPLE 3

a) A mixture of 34 g of ethyl 4-oxo-1-piperidinecarboxylate, 20 g of2-pyrimidinamine, 8 drops of acetic acid and 103.5 ml of methylbenzenewas stirred for 28 hours at reflux temperature using a water-separator.The reaction mixture was evaporated, yielding 50 g of ethyl4-(2-pyrimidinylimino)-1-piperidinecarboxylate as a residue (interm.18).

b) To a stirred and cooled (5-10° C.) mixture of 50 g of intermediate(18) in 76 ml of methanol were added portionwise 7.5 g of sodiumtetrahydroborate. Upon completion, stirring was continued first for 45minutes at room temperature and further for 3 hours at refluxtemperature. After cooling, the reaction mixture was poured into waterand the product was extracted twice with benzene. The combined extractswere washed with water, dried, filtered and evaporated. The residue wassolidified in a mixture of 2,2'oxybispropane and 2-propanone. Theproduct was filtered off and crystallized from benzene, yielding 7 g ofethyl 4-(2-pyrimidinylamino)-1-piperidinecarboxylate (interm. 19).

c) A mixture of 7 g of intermediate (19) and 80.5 ml of hydrobromic acidsolution (48%) was stirred for 2 hours at reflux temperature. Thereaction mixture was evaporated and the residue was taken up in water.The whole was basified with a diluted sodium hydroxide solution, whilecooling in an ice-bath. The product was extracted with dichloromethaneand the extract was dried, filtered and evaporated. The residue wasstirred in 2,2'-oxybispropane. The product was filtered off andconverted into the hydrochloride salt in 2-propanol. The salt wasfiltered off and crystallized from ethanol, yielding 2 g of(±)-N-(4-piperidinyl)-2-pyrimidinamine dihydrochloride hemihydrate; mp.268.5° C. (interm. 20).

EXAMPLE 4

a) 3 ml of N,N,N-trimethylbenzenemethanaminium hydroxide was addeddropwise to a stirred mixture of 60 g(±)-3,4-dihydro-N-(phenylmethyl)-2H-1-benzopyran-2-methanamine in 350 mlof 2-propenenitrile. After stirring for 4 days at reflux temperature,the reaction mixture was cooled and poured into 1,1'-oxybisethane. Thewhole was filtered over diatomaceous earth and the filtrate wasevaporated, yielding 21 g (28.6%) of(±)-3-[[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl](phenylmethyl)amino]propanenitrileas crude residue (interm. 21).

b) A mixture of 21 g of intermediate (21) in 250 ml of methanol washydrogenated in the presence of 5 g of Raney Nickel. After thecalculated amount of hydrogen was taken up, the catalyst was filteredoff and the filtrate was evaporated, yielding 20 g (94%) of(±)-N-[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]-N-(phenylmethyl)-1,3-propanediamine as cruderesidue (interm. 22).

c) A mixture of 10 g, of intermediate (22) 4.2 g of 2-chloropyrimidine,6 g of sodium carbonate and 100 ml of ethanol was stirred and heated for18 hours. The reaction mixture was cooled and the solvent wasevaporated. The residue was treated with water and the product wasextracted with 1,1'-oxybisethane. The extract was dried, filtered andevaporated, yielding 11 g (88.5%)of(±)-N-[(3,4-dihydro-2H-1-benzopyran-2yl)methyl]-N-(phenylmethyl)-N'-(2-pyrimidinyl)-1,3-propanediamineas a crude residue (interm. 23).

In a similar way there was also prepared:

    __________________________________________________________________________     ##STR20##                                                                     ##STR21##                                                                          ##STR22##                                                                             ##STR23##                                                                                 ##STR24##                                           __________________________________________________________________________    23   H, H                                                                                   ##STR25##  --                                                   24   H, H                                                                                   ##STR26##  .2HCl                                                25   H, H                                                                                   ##STR27##  .HCl; mp. 230.1° C.                           26   H, H                                                                                   ##STR28##  --                                                   27   7-CH.sub.2 CH.sub.3, H                                                                 ##STR29##  .2HCl.H.sub.2 O                                      28   H, H                                                                                   ##STR30##  --                                                   29   H, H                                                                                   ##STR31##  --                                                   30   H, H                                                                                   ##STR32##  --                                                   31   H, H                                                                                   ##STR33##  .2HCl. 1/2H.sub.2 O; mp. 189.6° C.            __________________________________________________________________________

EXAMPLE 5

a)To a stirred solution of 6 g of diphenyl cyanocarbonimidate in 50 mlof dichloromethane at room temperature were added portionwise 2.1 g ofpiperidine. Stirring was continued for 30 minutes at room temperature.The reaction mixture was evaporated and the residue was crystallizedfrom 2,2'-oxybispropane. The crystals were filtered off and dried,yielding 4.6 g (80.7%) of [phenoxy(1-piperidinyl)methylene]cyanamide;mp. 85.7° C. (interm. 32).

In a similar way was also prepared:

O-phenyl-N'-cyano-N,N-dimethylcarbamimidate (interm. 33).

b) A mixture of 4.0 g of(±)-N-[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]-1,3-propanediamine, 4.2g of intermediate (32) and 100 ml of methanol was stirred for 3 days atroom temperature. The reaction mixture was evaporated and the residuewas dissolved in dichloromethane. This solution was washed with anaqueous Na₂ CO₃ solution (15%). The organic layer was separated, dried,filtered and evaporated. The residue was purified twice by columnchromatography (silica gel; CH₂ Cl₂ /CH₃ OH 95:5). The eluent of thedesired fraction was evaporated and the residue was converted into theethanedioate salt (1:1) in 2-propane. The salt was filtered off andrecrystallized from methanol. The crystals were filtered off and dried,yielding 1.02 g (12.7%) of(±)-N'-cyano-N-[3-[[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]amino]propyl]-1-piperidinecarboxidimideethanedioate (1:1); mp. 176.0° C. (interm. 34).

In a similar way there were also prepared:

    __________________________________________________________________________     ##STR34##                                                                    Int.                                                                          No.                                                                              R.sup.7, R.sup.8                                                                      X  A           NR.sup.2 R.sup.3                                                                           physical data                          __________________________________________________________________________    34 H, H    CH.sub.2                                                                         NH(CH.sub.2).sub.3 NH                                                                      ##STR35##   mp. 176.0° C. ethanedioate                                             (1:1)                                  35 6-F, H  CH.sub.2                                                                         NH(CH.sub.2).sub.3 NH                                                                     NHCH.sub.2 CH.sub.3                                                                        mp. 117.8° C.                   36 H, H    CH.sub.2                                                                         NH(CH.sub.2).sub.3 NH                                                                     NHCH.sub.2 CH.sub.3                                                                        mp. 147.9° C./                                                         ethanedioate (1:1)                     37 H, H    O  NH(CH.sub.2).sub.3 NH                                                                     NHCH.sub.2 CH.sub.3                                                                        mp. 138.3° C./                                                         ethanedioate (1:1)                     38 H, H    CH.sub.2                                                                          ##STR36##  NH(CH.sub.2).sub.2 CH.sub.3                                                                --                                     39 H, H    CH.sub.2                                                                         NH(CH.sub.2).sub.3 NH                                                                     NHCH(CH.sub.3).sub.2                                                                       mp. 121.8° C.                   40 H, H    CH.sub.2                                                                         NH(CH.sub.2).sub.3 NH                                                                     NH(CH.sub.2).sub.2 CH.sub.3                                                                mp. 154.6° C./                                                         ethanedioate (1:1)                     41 H, H    CH.sub.2                                                                         NH(CH.sub.2).sub.3 NH                                                                     N(CH.sub.3).sub.2                                                                          mp. 171.1° C.                                                          ethanedioate (1:1)                     42 H, H    CH.sub.2                                                                         NH(CH.sub.2).sub.2 NH                                                                     NHCH.sub.3   mp. 158.0° C./HCl               43 H, H    CH.sub.2                                                                         NH(CH.sub.2).sub.3 NH                                                                     NHCH.sub.2 CCH                                                                             mp. 143.2° C.                   44 H, H    CH.sub.2                                                                         NH(CH.sub.2).sub.3 NH                                                                     NHCH.sub.2 CHCH.sub.2                                                                      mp. 164.7° C.                                                          ethanedioate (1:1)                     45 7-CH.sub.3, H                                                                         CH.sub.2                                                                         NH(CH.sub.2).sub.3 NH                                                                     N(CH.sub.3).sub.2                                                                          m.p. 190.2° C.                                                         ethanedioate (1:1)                     46 6-F, H  CH.sub.2                                                                         NH(CH.sub.2).sub.3 NH                                                                     N(CH.sub.3).sub.2                                                                          m.p. 173.2° C.                                                         (-) - (R)                                                                     ethanedioate (1:1)                                                            [α].sub.D.sup.20                                                        = -53.67°                                                              (c = 1% in DMF)                        47 7-CH.sub.2 CH.sub.3,H                                                                 CH.sub.2                                                                         NH(CH.sub.2).sub.3 NH                                                                     N(CH.sub.3).sub.2                                                                          m.p. 137.8° C.                                                         ethanedioate (1:1)                     48 7-CH.sub.2 CH.sub.3,H                                                                 CH.sub.2                                                                         NH(CH.sub.2).sub.3 NH                                                                     NHCH.sub.2 CH.sub.3                                                                        m.p. 91.7° C.                   49 7-CH.sub.2 CH.sub.3,H                                                                 CH.sub.2                                                                         NH(CH.sub.2).sub.3 NH                                                                     N(CH.sub.3).sub.2                                                                          m.p. 163.3° C.                                                         ethanedioate (1:2)                     50 H, H    CH.sub.2                                                                          ##STR37##  NHCH.sub.2 CH.sub.3                                                                        mp. 118.5° C.                   __________________________________________________________________________

EXAMPLE 6

A mixture of 3.1 g(±)-N"-cyano-N-[3-[[(3,4-dihydro-2H-1-benzopyran-2yl)methyl]amino]propyl]-N'-ethylguanidinein a solution of 10 ml hydrochloric acid in 2-propanol and 50 mlmethanol was stirred and refluxed for 30 minutes. The solvent wasevaporated. The residue was dissolved in water and this mixture wasalkalized with aqueous NaOH (10%). This mixture was extracted with CH₂Cl₂. The organic layer was separated, washed with water, dried (MgSO₄),filtered and the solvent was evaporated. The residue was purified bycolumn chromatography over silica gel (eluent: CH₂ Cl₂ / CH₃OH/(NH₃)90:10). The pure fractions were collected and the solvent wasevaporated. The residue was dissolved in 2-propanol and into thehydrochloric acid salt (1:2) with 2-propanol saturated with HCl. Thesalt was filtered off and recrystallized from 2-propanol. The crystalswere filtered off and dried, yielding 2.95g (±)-N-[[[3-[[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]amino]propyl]amino](ethylamino)methylene]urea dihydrochloride;mp. 182.2° C. (interm. 51).

In a similar manner there was also prepared:

(±)-N-[[[2-[[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]amino]ethyl]amino](ethylamino)methylene]ureadihydrochloride; mp. 200.2° C. (interm 52).

EXAMPLE 7

a) A mixture of 12.5 g of3,4-dihydro-N-(phenylmethyl)-2H-1-benzopyran-2-methanamine, 9 g of4-bromobutanenitrile, 200 ml of N,N-dimethylformamide and 10 ml ofN,N-diethylethanamine was stirred for 72 hour at room temperature. Thereaction mixture was evaporated and the residue was partitioned between1,1'-oxybisethane and water. The organic layer was separated, dried,filtered and evaporated, yielding 11 g (68.7%) of(±)-4-[[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl](phenylmethyl)amino]-butanenitrile (interm. 53).

b) A mixture of 11 g of intermediate (53) and 250 ml tetrahydrofuran washydrogenated in the presence of 2 g of Raney Nickel. After thecalculated amount of hydrogen was taken up, the catalyst was filteredoff and the filtrate was evaporated. The residue was partitioned between1,1'-oxybisethane and water. The organic layer was separated, dried,filtered and evaporated, yielding 10 g (90.6%) of(±)-N-[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]1-N-(phenylmethyl)-1,4-butanediamine(interm. 54).

c) A mixture of 10 g of intermediate (54), 5.4 g of 2-chloropyrimidine,8 g of sodium carbonate and 250 ml of ethanol was stirred for 18 hoursat reflux temperature. The reaction mixture was evaporated and theresidue was partitioned between 1,1'-oxybisethane and water. The organiclayer was separated, dried, filtered and evaporated, yielding 10.4 g(83.3%) of (±)-N-[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]-N-(phenyhnethyl)-N'-(2-pyrimidinyl)-1,4-butanediamine (interm.55).

In a similar way there were also prepared:

    __________________________________________________________________________     ##STR38##                                                                     ##STR39##                                                                          ##STR40##                                                                         ##STR41##                                                                        ##STR42##                                                                        ##STR43##                                                                       ##STR44##                                                                                ##STR45##                                        __________________________________________________________________________    55   H, H                                                                              CH.sub.2                                                                         H  4                                                                                ##STR46## --                                                56   H, H                                                                              CH.sub.2                                                                         H  2                                                                                ##STR47## (S)                                               57   6-F, H                                                                            CH.sub.2                                                                         H  2                                                                                ##STR48## [α].sub.D.sup.20 = 54.79° (c =                                   1% in CH.sub.3 OH) mp. 155.9° C./ (+)                                  - (S) 2HCl. 1/2 H.sub.2 O                         58   H, H                                                                              CH.sub.2                                                                         H  2                                                                                ##STR49## (R)                                               59   6-F, H                                                                            CH.sub.2                                                                         H  2                                                                                ##STR50## mp. 173.8° C. (-) - (R) 2HCl               60   H, H                                                                              O  H  2                                                                                ##STR51## --                                                61   H, H                                                                              CH.sub.2                                                                         H  2                                                                                ##STR52## mp. 175.6° C. 2HCl . 1/2 H.sub.2 O         62   H, H                                                                              CH.sub.2                                                                         CH.sub.3                                                                         2                                                                                ##STR53## --                                                63   H, H                                                                              CH.sub.2                                                                         H  5                                                                                ##STR54## --                                                64   H, H                                                                              CH.sub.2                                                                         H  4                                                                                ##STR55## (R) . HCl                                         65   6-F, H                                                                            CH.sub.2                                                                         H  2                                                                                ##STR56## mp. 219.5° C. (-) - (R).2HCl               66   H, H                                                                              CH.sub.2                                                                         H  5                                                                                ##STR57## (R) . HCl                                         __________________________________________________________________________

EXAMPLE 8

a) A mixture of 18 g of intermediate (12), 60 g of 2-propenenitrile and400 ml of ethanol was stirred for 4 hours at reflux temperature. Thereaction mixture was evaporated and the residue was dried, yielding 20 g(84%) of(-)-(R)-3-[[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]amino]propanenitrile(interm. 67).

b) A mixture of 20 g intermediate (67) and 300 ml of methanol washydrogenated in the presence of 5 g of Raney Nickel. After thecalculated amount of hydrogen was taken up, the catalyst was filteredoff and the filtrate was evaporated, yielding 21 g (100%) of(-)-(R)-N-[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]-1,3-propanediamineas crude residue (interm. 68).

In a similar way there were also prepared:

    ______________________________________                                         ##STR58##                                                                    Int. No.        R.sup.7, R.sup.8                                                                            X                                               ______________________________________                                        68              H, H          CH.sub.2                                        69              6-F, H        CH.sub.2                                        70              H, H          O                                               71              H, H          CH.sub.2                                        72              6-OCH.sub.3, H                                                                              CH.sub.2                                        73              H, H          CH.sub.2                                        ______________________________________                                    

EXAMPLE 9

a) To a stirred mixture of 38.6 g ofN,N-dibenzyI-N'-(3,4-dihydro-2H-1-benzopyran-2-yl)-1,2-ethanediamine,1.2 g of N,N-dimethyl-4-pyridinamine and 300 ml of acetonitrile at roomtemperature, was added dropwise a solution of 24 g ofbis(1,1-dimethylethyl) dicarbonate in 50 ml of acetonitrile. Afterstirring for 3 hours, the reaction mixture was evaporated and theresidue was diluted with water. The product was extracted with1,1'oxybisethane and the extract was dried, filtered and evaporated,yielding 50 g (100%) of (±)-1,1-dimethylethyl [2-[bis(phenylmethyl)amino]ethyl][(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]carbamate as cruderesidue (interm. 74).

b) A mixture of 14.0 g of intermediate (74) and 150 ml of methanol washydrogenated in the presence of 2 g of palladium-on-charcoal catalyst(10%). After the calculated amount of hydrogen was taken up, thecatalyst was filtered off and the filtrate was evaporated. The residuewas purified by column chromatography (silica gel; CH₂ Cl₂ / CH₃ OH(NH₃)95:5). The eluent of the desired fraction was evaporated, yielding 1.22g of (±)-1,1-dimethylethyl (2-aminoethyl)[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]carbamate (interm. 75).

c) To a mixture of 7.0 g of intermediate (75) and 100 ml oftrichloromethane were added 3.3 g of dimethylcyanocarbonimidodithionate. After stirring for 48 hours at refluxtemperature, the reaction mixture was evaporated. The residue waspurified by column chromatography (silica gel; CH₂ Cl₂ /CH₃ OH 99:1).The eluent of the desired fraction was evaporated, yielding 9.09 g(96.5%) of (±)-1,1-dimethylethyl [2-[[(cyanoimino)-(methylthio)methyl]amino]ethyl][(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]carbamate(interm. 76).

d) To a mixture of 18 g of intermediate (76) and 150 ml of ethanol wereadded 40 ml of an aqueous solution of ethanamine (70%). After stirringfor 16 hours at reflux temperature, the reaction mixture was evaporatedand the residue was dissolved in dichloromethane. This solution waswashed with water, dried, filtered and evaporated. The residue waspurified by column chromatography (silica gel; CH₂ Cl₂ /CH₃ OH 95:5).The eluent of the desired fraction was evaporated and the residue wassolidified from 2,2'-oxybispropane, yielding 13.9 g (77.2%) of(±)-1,1-dimethylethyl[2-[[(cyanoimino)(ethylamino)methyl]amino]ethyl][(3,4-dihydro-2H-1-benzopyran-2yl)methyl]carbamate;mp. 115.4° C. (interm. 77).

e) A mixture of 6 g of intermediate (77), 20 ml of 2-propanol saturatedwith HCl and 200 ml of methanol was stirred for 30 minutes at refluxtemperature. The reaction mixture was evaporated and the residue wascrystallized from methanol. The product was filtered off and washed withmethanol and 2,2'-oxybispropane, yielding 4.3 g (73%) of(±)-N-[[[2-[[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]amino]ethyl]amino](ethylamino)methylene]ureadihydrochloride; mp. 200.2° C. (interm. 78).

B. Preparation of the Finals EXAMPLE 10

A mixture of 7.4 g of N¹-[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]-1,2-ethanediamine, 4.1 g2-chloropyrimidine, 4.2 g of sodium carbonate and 50.6 ml of ethanol wasstirred for 4 hours at reflux temperature. The reaction mixture wasevaporated. The residue was purified by column chromatography (silicagel; CHCl₃ /CH₃ OH 90:10). The eluent of the desired fraction wasevaporated and the residue was converted into the hydrochloride salt in2-propanol. The salt was filtered off and dried in vacuo, yielding 4.4 g(33.3%) of(±)-N-[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]-N'-(2-pyrimidinyl)-1,2-ethanediaminedihydrochloride hemihydrate; mp. 192.7° C. (comp. 1).

EXAMPLE 11

A mixture of 8.5 g of 3,4-dihydro-2H-benzopyran-2-carbonyl chloride, 30ml of N,N-dimethylacetamide and 100 ml of 2,2'-oxybispropane washydrogenated in the presence of 2 g of palladium-on-charcoal catalyst(10%) and 2 ml of a solution of thiophene in methanol (4%). After thecalculated amount of hydrogen was taken up, the catalyst was filteredoff and the filtrate was added to a mixture of 5 g of (±)-N¹-(2-pyrimidinyl)-1,2-propanediamine and 150 ml of methanol. The wholewas hydrogenated in the presence of 2 g of palladium-on-charcoalcatalyst (10%) and 5 g of potassium acetate. After the calculated amountof hydrogen was taken up, the catalyst was filtered off and the filtratewas evaporated. The residue was dissolved in 1,1'-oxybisethane, washedwith an aqueous NaOH solution, dried, filtered and evaporated. Theresidue was converted into the ethanedioate salt (1:2) in 2-propanone.The salt was filtered off and dried in vacuo at 60° C., yielding 8.7 g(55.1%) of (±)-N1-[(3,4-dihydro-2H-¹ -benzopyran-2-yl)methyl]-N²-(2-pyrimidinyl)-1,2-propanediamine ethanedioate(1:2), mp. 150.2° C.(comp. 119).

EXAMPLE 12

A mixture of 4.8g 6-bromo-3,4-dihydro-2H-1-benzopyran-2-carboxaldehydeand 3.1g N-2-pyrimidinyl-1,3-propanediamine in 200ml methanol washydrogenated with 2g platinum on activated carbon (5%) as a catalyst inthe presence of 2ml of a solution of thiophene in methanol (4%). Afteruptake of H2, the catalyst was filtered off. The filtrate wasevaporated. The residue was dissolved in 2-propanone and converted intothe ethanedioic acid salt (1:2). The salt was filtered off andrecrystallized from ethanol/water. The crystals were filtered off anddried, yielding 2.7g (18.8%)(±)-N-[(6-bromo-3,4-dihydro-2H-1-benzopyran-2-yl)methyl]-N'-(2-pyrimidinyl)-1,3propanediamineethanedioate(1:2); nap. 215.3° C. (comp. 20).

EXAMPLE 13

A mixture of 3 g N-2-pyrimidinyl-1,3-propanediamine in 150 ml methanoland 10 ml of a solution of hydrochloric acid in 2-propanol washydrogenated with 2 g palladium on activated charcoal (5%) as acatalyst. After uptake of H₂, the catalyst was filtered off. A solutionof 4.8 g 6-bromo-3,4-dihydro-2H-1-benzopyran-2-carboxaldehyde in 100mlmethanol was added to the filtrate. 10 g Potassium acetate was added andthe resulting mixture was hydrogenated with 2 g platinum on activatedcharcoal (5%) as a catalyst, in the presence of 2 ml of a solution ofthiophene in methanol (4%). After uptake of H2, the catalyst wasfiltered off. The solvent was evaporated and the residue was dissolvedin a mixture of H₂ O/CH₂ Cl₂. This solution was alkalized with NaOH. Theorganic layer was separated, dried, filtered and the solvent wasevaporated. The residue was dissolved in 2-propanone and converted intothe ethanedioic acid salt (1:2). The salt was filtered off and dried.This fraction was recrystallized from ethanol/water. The crystals werefiltered off and dried, yielding 3.5 g (31.2%) of(±)-N-[(6-bromo-3,4-dihydro-2H-1-benzopyran-2-yl)methyl]-N'-(1,4,5,6-tetrahydro-2-pyrimidinyl)-1,3-propanediamineethanedioate(1:2); mp. 204.8° C. (comp. 56).

EXAMPLE 14

A mixture of 7.9 g of 3,4-dihydro-2H-1-benzopyran-2-methanol4-methylbenzenesulfonate(ester), 4.5 gN-(4-piperidinyl)-2-pyrimidinamine, 5.3 g of sodium carbonate and 100 mlof 4-methyl-2-pentanone was stirred overnight at reflux temperature. Thereaction mixture was evaporated and the residue was diluted with water.The product was extracted with dichloromethane and the extract wasdried, filtered and evaporated. The residue was purified by columnchromatography (silica gel; CH₂ Cl₂ 100%). The eluent of the desiredfraction was evaporated ,and the residue was crystallized fromacetonitrile. The product was filtered off and dried, yielding 28 g(98.8%) of(±)-N-[1-[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]-4-piperidinyl]-2-pyrimidinamine;mp. 141.9° C. (comp. 128).

EXAMPLE 15

A mixture of 8.4 g of(-)-(R)-N-(6-fluoro-3,4-dihydro-2H-1-benzopyran-2-yl)methyl-N-phenylmethyl-N'-(2-pyrimidinyl)-1,2-ethanediamine and 150 mlmethanol was hydrogenated in the presence of 2 g ofpalladium-on-charcoal catalyst (10%). After the calculated amount ofhydrogen was taken up, the catalyst was filtered off and the filtratewas evaporated. The residue was purified by column chromatography(silica gel; CH₂ Cl₂ /CH₃ OH 90:10). The eluent of the desired fractionwas evaporated and the residue was crystallized from 2,2'-oxybispropane.The product was filtered off and dried, yielding 3.5 g (55.1%) of(-)-(R)-N-[(6-fluoro-3,4-dihydro-2H-1-benzopyran-2yl)methyl]-N'-(2-pyrimidinyl)-1,2-ethanediamine;mp. 103.2° C. [α]_(D) ²⁰ =-76.58° (conc.=1% in CH₃ OH) (comp. 46).

EXAMPLE 16

A mixture of 3.6 g of(-)-(R)-N-[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]-N'-(2-pyrimidinyl)-1,3-propanediaminedihydrochloride hemihydrate in 150 ml of methanol and 20 ml of2-propanol saturated with HCl was hydrogenated in the presence of 1.5 gof palladium-on-charcoal catalyst (2%). After the calculated amount ofhydrogen was taken up, the catalyst was filtered off and the filtratewas evaporated. The product was crystallized from acetonitrile, filteredoff and dried, yielding 2.7 g (74.0%) of(-)-(R)-N-[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]-N'-(1,4,5,6-tetrahydro-2-pyrimidinyl)-1,3-propanediaminedihydrochloride hemihydrate; mp. 200.2° C. [α]_(D) ²⁰⁼⁻ 60.97° (conc.=1% in CH₃ OH) (comp. 62).

EXAMPLE 17

A mixture of 7.8 g ofN-(3,4-dihydro-2H-1-benzopyran-2-yl)methyl-N-phenylmethyl-N'-(2-pyrimidinyl)-1,3-propanediamine,200 ml methanol and 10 ml of 2-propanol saturated with HCl washydrogenated in the presence of 2 g of palladium-on-charcoal catalyst(5%). After the calculated amount of hydrogen was taken up, the catalystwas filtered off and the filtrate was evaporated. The residue wasconverted into the dihydrochloride salt in 2-propanol by adding2-propanol saturated with hydrochloric acid. The salt was filtered offand dried, yielding 2.9 g (38.0%) of(±)-N-[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]-N'-(1,4,5,6-tetrahydro-2-pyrimidinyl)-1,3-propanediaminedihydrochloride; mp. 227.0° C. (comp. 95).

EXAMPLE 18

A solution of 6.9 g of(±)-N-[(3,4-dihydro-6-methoxy-2H-1-benzopyran-2-yl)methyl]-N'-(2-pyrimidinyl)-1,3-propanediaminein 50 ml of dichloromethane was added dropwise to a mixture of 150 ml ofa boron tribromide solution in dichloromethane (1M) and 250 mldichloromethane, stirred under a nitrogen atmosphere at 0° C. Thereaction mixture was stirred for 2 hours at room temperature. Theresulting precipitate was filtered off and stirred in a mixture of 150 gof ice, 42 g of sodium chloride and 175 ml of NH₄ OH. Dichloromethanewas added and the whole was filtered over diatomaceous earth. The layerswere separated and the aqueous layer was extracted with dichloromethane.The combined organic layers were dried, filtered and evaporated. Theresidue was purified by column chromatography (silica gel; CH₂ Cl₂ /CH₃OH/(NH₃) 95:5). The eluent of the desired fraction was evaporated andthe residue was converted into the ethanedioate salt in 2-propanone. Thesalt was filtered off and dried in vacuo at 60° C., yielding 3.0 g(28.9%) of(±)-3,4-dihydro-2-[[[3-(2-pyrimidinylamino)propyl]amino]methyl]-2H-1-benzopyran-6-olethanedioate (1:2); mp. 170.0° C. (comp. 49).

EXAMPLE 19

A mixture of 2.6 g of(±)-N"-cyano-N-[3-[[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]amino]propyl]-N'-(1-methylethyl)guanidinein 20 ml of hydrochloric acid 6N was stirred for 2 hours at refluxtemperature. The reaction mixture was evaporated and the residue wasdissolved in 10 ml of methanol. This solution was filtered and thefiltrate was evaporated. The oily residue was dissolved in 10 ml ofethanol. The mixture was filtered and the filtrate was evaporated,yielding 1.32 g (44.4%) of(±)-N-[3-[[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]amino]propyl]-N'-(1-methylethyl)-guanidinedihydrochloride; mp. 97.5° C. (comp. 150).

EXAMPLE 20

2.3g(±)-N-[(6-fluoro-3,4-dihydro-2H-1-benzopyran-2-yl)methyl]-1,3-propanediamineand 1.6g iodine monochloride were dissolved in 50ml acetic acid. Thissolution was stirred and refluxed overnight. The solvent was evaporated.The residue was purified by column chromatography over silica gel(eluent: CH₂ Cl₂ /CH₃ OH 99:1 upgrading to 95:5). Two desired fractionswere collected and the solvent was evaporated. De residue (±50% pure)wasrecrystallized from ethanol. The crystals were filtered off and dried,yielding 0.650g (20.1%) of(±)-N-[(6-fluoro-3,4-dihydro-2H-1-benzopyran-2-yl)methyl]-N'-(5-iodo-2-pyrimidinyl)-1,3-propanediaminemonohydrochloride; mp. 228.2° C. (comp. 155).

EXAMPLE 21

A mixture of 0.250g palladium on activated carbon 10% in 50ml methanolwas stirred under vacuum and rinsed with H₂. 5 ml of 2-propanolsaturated with HCl was added. A solution of 0.5g(±)-3,4-dihydro-2-[[[3-(2-pyrimidinylamino)propyl]amino]methyl]-2H-1-benzopyran-6-carbonitriledihydrochloride hemihydrate in 5 ml methanol was added dropwise. Thereaction mixture was hydrogenated while stirring for 2 hours. Afteruptake of H2, the mixture was filtered over dicalite.

The filter residue was washed with CH₃ OH. The filtrate was evaporatedand the residue was stirred in 10ml CH₃ OH, filtered over a pleatedpaper filter and washed with 5ml CH₃ OH. The filtrate was evaporated.The residue was stirred in 10 ml 2-propanone, then filtered over a glassfilter. The filter residue was dried, yielding 0.427g (82.2%); mp.240.1° C. (comp. 102).

EXAMPLE 22

50 ml Methylbenzene was added to 4.3 g (±)-methyl8-ethynyl-6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylate, thenevaporated. The residue was dissolved in 100 ml methylbenzene and thissolution was cooled to -70° C. A solution of 25 mlhydrobis(2methylpropyl)aluminum hydride in methylbenzene (20%) was addeddropwise. The reaction mixture was stirred for 1 hour at -70° C. 10 mlMethanol was added dropwise and the temperature was allowed to reachroom temperature. The reaction mixture was poured out into 150 ml waterand extracted with diethyl ether. The separated organic layer was dried,filtered and the solvent was evaporated. The residue was dissolved inmethanol and 1.95 g N-(2-pyrimidinyl)-1,3-propanediamine was added. Thismixture was hydrogenated at room temperature with 1 g palladium onactivated carbon (10%) as a catalyst in the presence of a solution of 4ml of thiophene (4%). After uptake of H₂, the catalyst was filtered off.The filtrate was evaporated. The residue was purified by columnchromatography over silica gel (eluent: CH₂ Cl₂ /CH₃ OH 95:5 upgradingto 90:10). The pure fractions were collected and the solvent wasevaporated. The residue was dissolved in 80 ml 2-propanone and convertedinto the ethanedioic acid salt (1:1). The salt was filtered off, washedwith 2opropanone and 2,2'-oxybispropane, then dried, yielding 4.3 g(63.1%) of(±)-N-[(8-ethyl-6-fluoro-3,4-dihydro-2H-1-benzopyran-2-yl)methyl]-N'-2-pyrimidinyl-1,3-propanediamineethanedioate (1:2); mp. 210.8° C. (comp. 54).

All compounds listed in Tables 1 to 5 were prepared following methods ofpreparation described in Examples 10 to 22, as indicated in the columnEx. No.

                                      TABLE 1                                     __________________________________________________________________________     ##STR59##                                                                    Co.                                                                              Ex.                                                                        No.                                                                              No.                                                                              R.sup.7                                                                              R.sup.8                                                                              X  s physical data                                        __________________________________________________________________________    1  10 H      H      CH.sub.2                                                                         2 mp. 192.7° C./. 2 HCl . 1/2 H2O               2  10 H      H      CH.sub.2                                                                         3 mp. 193.4° C./[α].sub.D.sup.20 =                                 -63.46°                                                                (c = 1% in CH.sub.3 OH)                                                       (-) - (R).2 HCl .  1/2H.sub.2 O                      3  10 6-F    H      CH.sub.2                                                                         3 mp. 139.9° C./ .2 HCl .  1/2H.sub.2 O         4  10 H      H      O  3 --                                                   5  10 H      H      CH.sub.2                                                                         3 mp. 223.2° C./[α].sub.D.sup.20                                   =48.63°                                                                (c = 0.1% in CH.sub.3 OH)/(+) - (S) . HCl            6  10 6-OCH.sub.3                                                                          H      CH.sub.2                                                                         3 mp. 190.6° C./. HCl                           7  10 7-CH.sub.3                                                                           H      CH.sub.2                                                                         3 mp. 212.0° C./ethanedioate (1:2)              8  10 7-C.sub.2 H.sub.5                                                                    H      CH.sub.2                                                                         3 mp. 141.4° C./[α].sub.D.sup.20 =                                 67.48°                                                                 (c = 1% in CH.sub.3 OH)/(+) - (S) .2 HCl                                      .  1/2 H.sub.2 O                                     9  10 7-C.sub.2 H.sub.5                                                                    H      CH.sub.2                                                                         3 mp. 154.9° C./[α].sub.D.sup.20 =                                 -69.37°                                                                (c = 1% in CH.sub.3 OH)/(-) - (R) .2 HCl             10 11 H      H      -- 3 mp. 145.8° C./ .2 HCl .  1/2 H.sub.2 O        11 11 6-F    H      CH.sub.2                                                                         6 mp. 170.3 C./ . 2HCl                                 12 11 6-F    H      CH.sub.2                                                                         3 mp. 197.5° C./(+) - (S) .2 HCl                13 11 6-F    H      CH.sub.2                                                                         3 mp. 200.9° C./(-) - (R) .2 HCl                14 11 6-F    H      CH.sub.2                                                                         4 mp. 171.1° C./[α].sub.D.sup.20 =                                 -64.54°                                                                (c = 1% in CH.sub.3 OH)/(-) - (R) .2 HCl             15 11 6-F    H      CH.sub.2                                                                         4 mp. 177.4° C./[α].sub.D.sup.20 =                                 66.26°                                                                 (c = 1% in CH.sub.3 OH)/(+) - (S) .2 HCl             16 11 7-C.sub.2 H.sub.5                                                                    H      CH.sub.2                                                                         3 mp. 125.5° C./ .2 HCl .  1/2H.sub.2 O         17 11 7-C.sub.2 H.sub.5                                                                    H      CH.sub.2                                                                         5 mp. 177.1° C./ .2 HCl                         18 11 7-C.sub.2 H.sub.5                                                                    H      CH.sub.2                                                                         4 mp. 140.1° C./ .2 HCl                         19 11 H      H      O  4 mp. 208.1° C./ethanedioate (1:1)              20 12 6-Br   H      CH.sub.2                                                                         3 mp. 215.3° C./ethanedioate (1:2)              21 12 6-CH.sub.3                                                                           H      CH.sub.2                                                                         3 mp. 207.1° C./ethanedioate (1:1)              22 12 7-F    H      CH.sub.2                                                                         3 mp. 217.3° C./ethanedioate (1:1)              23 12 5-CH.sub.3                                                                           7-CH.sub.3                                                                           CH.sub.2                                                                         3 mp. 186.6° C./. 2 HCl                         24 12 H      8-OCH.sub.3                                                                          CH.sub.2                                                                         3 mp. 216.1° C./. 2 HCl                         25 12 H      H      CH.sub.2                                                                         9 mp. 159.7° C./ 2 HCl .  1/2 H.sub.2 O         26 12 H      H      CH.sub.2                                                                         8 mp. 152.9° C./ 2 HCl                          27 12 7-OCH.sub.3                                                                          H      CH.sub.2                                                                         3 ethanedioate (1:1)                                   28 12 H      H      CH.sub.2                                                                         10                                                                              mp. 164.9° C./.2 HCl                          29 12 H      H      CH.sub.2                                                                         7 mp. 152.4° C./.2 HCl                          30 12 6-F    8-Br   CH.sub.2                                                                         3 mp. 145.0° C.                                 31 12 H      8-CH.sub.3                                                                           CH.sub.2                                                                         3 ethanedioate (1:2)                                   32 12 5-OCH.sub.3                                                                          H      CH.sub.2                                                                         3 mp. 219.9° C./ethanedioate (1:1)              33 12 H      8-CH.sub.3                                                                           CH.sub.2                                                                         3 mp. 219.3° C./ethanedioate (1:1)              34 12 7-CH(CH.sub.3).sub.2                                                                 H      CH.sub.2                                                                         3 mp. 127.0° C./. 2 HCl . H.sub.2 O             35 12 7-C.sub.4 H.sub.9                                                                    H      CH.sub.2                                                                         3 mp. 170.9° C./. 2 HCl . H.sub.2 O             36 12 7-C.sub.3 H.sub.7                                                                    H      CH.sub.2                                                                         3 .2 HCl . 2 H.sub.2 O                                 37 12 7-C(CH.sub.3).sub.3                                                                  H      CH.sub.2                                                                         3 .2 HCl                                               38 12 7-CH.sub.3                                                                           8-CH.sub.3                                                                           CH.sub.2                                                                         3 .2 HCl                                               39 12 H      H      CH.sub.2                                                                         3 mp. 120.9° C./[α].sub.D.sup.20 =                                 -15.78°                                                                (c = 1% in methanol)/                                                         (-) - (R) cyclohexylsulfamate (1:2)                  40 12 6-F    8-NHCOCH.sub.3                                                                       CH.sub.2                                                                         3 mp. 172.9° C./ethanedioate (1:2)              41 14 6-CN   H      CH.sub.2                                                                         3 mp. 175.1° C./. 2 HCl .  1/2 H.sub.2 O        42 14 6-Br   8-NO.sub.2                                                                           CH.sub.2                                                                         3 mp. 195.1° C./ .2 HCl                         43 15 H      H      CH.sub.2                                                                         2 mp. 201.7° C./[α].sub.D.sup.20 =                                 89.14°                                                                 (c = 1% in CH.sub.3 OH)/ (+) - (S) . 2 HCl           44 15 6-F    H      CH.sub.2                                                                         2 mp. 102.9° C./[α].sub.D.sup.20 =                                 80.32°                                                                 (c = 1% in CH.sub.3 OH)/ (+) - (S)                   45 15 H      H      CH.sub.2                                                                         2 mp. 204.5° C./[α].sub.D.sup.20 =                                 -63.45°                                                                (c = 0.5% in DMF)/ (-) - (R) . 2 HCl                 46 15 6-F    H      CH.sub.2                                                                         2 mp. 103.2° C./[α].sub.D.sup.20 =                                 -76.58°                                                                (conc. = 1% in CH.sub.3 OH)/ (-) - (R)               47 15 H      H      CH.sub.2                                                                         3 mp. 142.9° C./ .2 HCl .  1/2 H.sub.2 O        48 15 H      H      CH.sub.2                                                                         4 mp. 140.8° C./ .2 HCl . H.sub.2 O             49 18 6-OH   H      CH.sub.2                                                                         3 mp. 170.0° C./ethanedioate (1:2)              50 18 H      8-OH   CH.sub.2                                                                         3 mp. 170.5° C./ . 2 HCl                        51 18 7-OH   H      CH.sub.2                                                                         3 --                                                   52 18 5-OH   H      CH.sub.2                                                                         3 mp. 139.1° C./ethanedioate (1:2)              53 21 H      8-NH.sub.2                                                                           CH.sub.2                                                                         3 mp. 270.7° C./ .3 HCl . H.sub.2 O             54 22 6-F    8-CH.sub.2 CH.sub.3                                                                  CH.sub.2                                                                         3 mp. 210.8° C./ethanedioate                    __________________________________________________________________________                             (1:2)                                            

                                      TABLE 2                                     __________________________________________________________________________     ##STR60##                                                                    Co Ex                                                                         No No                                                                              R.sup.7                                                                              R.sup.8                                                                              X  s physical data                                         __________________________________________________________________________    55 10                                                                              6-OCH.sub.3                                                                          H      CH.sub.2                                                                         3 mp. 199.9° C./ . 2 HBr                         56 13                                                                              6-Br   H      CH.sub.2                                                                         3 mp. 204.8° C./ ethanedioate (1:2)              57 16                                                                              H      H      CH.sub.2                                                                         2 mp. 216.7° C./ . 2 HCl                         58 16                                                                              H      H      CH.sub.2                                                                         2 mp. 197.8° C./ [α].sub.D.sup.20 =                                53.59°                                                                 (c = 0.5% in CH.sub.3 OH)/ (+) - (S). 2 HCl           59 16                                                                              H      H      CH.sub.2                                                                         2 mp. 199.2° C./ [α].sub.D.sup.20 =                                -52.66°                                                                (c = 0.5% in DMF)/ (-) - (R). 2 HCl                   60 16                                                                              6-F    H      CH.sub.2                                                                         2 mp. 215.1° C./ [α].sub.D.sup.20 =                                68.31°                                                                 (c = 1% in CH.sub.3 OH)/ (+) - (S). 2 HCl             61 16                                                                              6-F    H      CH.sub.2                                                                         2 mp. 213.19° C./ [α].sub.D.sup.20 =                               -64.80°                                                                (c = 1% in CH.sub.3 OH)/ (-) - (R). 2 HCl             62 16                                                                              H      H      CH.sub.2                                                                         3 mp. 200.2° C./ [α].sub.D.sup.20 =                                -60.97°                                                                (c = 1% in CH.sub.3 OH)                                                       (-) - (R) . 2HCl .  1/2 H.sub.2 O                     63 16                                                                              6-F    H      CH.sub.2                                                                         3 mp. 226.3° C./ . 2 HCl                         64 16                                                                              H      H      O  3 mp. 164.7° C./ . 2 HCl                         65 16                                                                              H      H      CH.sub.2                                                                         3 mp. 162.0° C./ [α].sub.D.sup.20 =                                65.83°                                                                 (c = 1% in CH.sub.3 OH)                                                       (+) - (S) . 2 HCl . H.sub.2 O                         66 16                                                                              H      H      -- 3 mp. 167.9° C./ . 2 HCl .  1/2 H.sub.2 O        67 16                                                                              7-CH.sub.3                                                                           H      CH.sub.2                                                                         3 mp. 216.4° C./ .ethanediaote (1:2)             68 16                                                                              6-F    H      CH.sub.2                                                                         6 mp. 201.1° C./ .2 HCl                          69 16                                                                              6-F    H      CH.sub.2                                                                         3 mp. 228.9° C./ [α].sub.D.sup.20 =                                65.47°                                                                 (c = 1% in CH.sub.3 OH)                                                       .(+) - (S) . 2 HCl                                    70 16                                                                              6-F    H      CH.sub.2                                                                         3 mp. 228.9° C./ [α].sub.D.sup.20 =                                -65.45°                                                                (c = 1% in CH.sub.3 OH)                                                       (-) - (R). 2 HCl                                      71 16                                                                              6-F    H      CH.sub.2                                                                         4 mp. 203.2° C./ [α].sub.D.sup.20 =                                65.81°                                                                 (+) - (S) . 2 HCl                                     72 16                                                                              7-F    H      CH.sub.2                                                                         3 mp. 221.2° C./ ethanedioate (1:2)              73 16                                                                              7-CH.sub.2 CH.sub.3                                                                  H      CH.sub.2                                                                         3 mp. 155.3° C./ .2 HCl.  1/2H.sub.2 O           74 16                                                                              5-CH.sub.3                                                                           7-CH.sub.3                                                                           CH.sub.2                                                                         3 mp. 195.4° C./ . 2 HCl                         75 16                                                                              H      H      CH.sub.2                                                                         9 mp. 154.6° C./ . 2HCl                          76 16                                                                              H      8-OCH.sub.3                                                                          CH.sub.2                                                                         3 mp. 130.0° C./ . 2 HCl.  1/2 H.sub.2 O         77 16                                                                              H      H      CH.sub.2                                                                         8 mp. 139.5° C./ . 2 HCl.  1/2 H.sub.2 O         78 16                                                                              H      7-OCH.sub.3                                                                          CH.sub.2                                                                         3 mp. 213.6° C./ ethanedioate (1:2)              79 16                                                                              H      H      CH.sub.2                                                                         10                                                                              mp. 132.3° C./ . 2 HCl.  1/2 H.sub.2 O         80 16                                                                              H      H      CH.sub.2                                                                         7 mp. 113.0° C./ . 2 HCl.  1/2 H.sub.2 O         81 16                                                                              7-CH.sub.2 CH.sub.3                                                                  H      CH.sub.2                                                                         4 mp. 157.2° C./ .2 HCl                          82 16                                                                              7-CH.sub.2 CH.sub.3                                                                  H      CH.sub.2                                                                         5 mp. 125.1° C./ .2 HCl                          83 16                                                                              6-OH   H      CH.sub.2                                                                         3 mp. 241.3° C./ .2 HCl                          84 16                                                                              H      8-CH.sub.3                                                                           CH.sub.2                                                                         3 mp. 183.8° C./ ethanedioate (1:2)              85 16                                                                              5-OCH.sub.3                                                                          H      CH.sub.2                                                                         3 mp. 183.2° C./ ethanedioate (1:2)              86 16                                                                              7-CH(CH.sub.3).sub.2                                                                 H      CH.sub.2                                                                         3 mp. 171.0° C./ . 2 HCl.  1/2 H.sub.2 O         87 16                                                                              7-C.sub.4 H.sub.9                                                                    H      CH.sub.2                                                                         3 mp. 178.2° C./ . 2 HCl                         88 16                                                                              7-C.sub.3 H.sub.7                                                                    H      CH.sub.2                                                                         3 mp. 161.2° C./ . 2 HCl.  1/2 H.sub.2 O         89 16                                                                              7-C(CH.sub.3).sub.3                                                                  H      CH.sub.2                                                                         3 mp. 191.5° C./ . 2 HCl . H.sub.2 O             90 16                                                                              7-CH.sub.3                                                                           8-CH.sub.3                                                                           CH.sub.2                                                                         3 mp. 202.7° C./ . 2 HCl . H.sub.2 O             91 16                                                                              H      H      CH.sub.2                                                                         3 mp. 165.9° C./ [α].sub.D.sup.20 =                                -26.40°                                                                (c = 1% in methanol)/                                                         (-) - (R) cyclohexylsulfamate (1:2)                   92 16                                                                              7-C.sub.2 H.sub.5                                                                    H      CH.sub.2                                                                         3 mp. 172.9° C./ [α].sub.D.sup.20 =                                -76.83°                                                                (c = 1% in methanol)/ (-) - (R) .2 HCl                93 16                                                                              6-F    8-NHCOCH.sub.3                                                                       CH.sub.2                                                                         3 mp. 202.2° C./ ethanedioate (1:2)              94 16                                                                              6-F    8-C.sub.2 H.sub.5                                                                    CH.sub.2                                                                         3 mp. 204.1° C./ ethanedioate (1:2)              95 17                                                                              H      H      CH.sub.2                                                                         3 mp. 227.0° C./ . 2 HCl                         96 17                                                                              H      H      O  2 mp. 220.8° C./ . 2 HCl                         97 17                                                                              H      H      CH.sub.2                                                                         4 mp. 96.2° C./ . 2 HCl .  3/2 H.sub.2 O         98 17                                                                              H      H      CH.sub.2                                                                         5 mp. 157.5° C./ . 2 HCl .  1/2 H.sub.2 O        99 17                                                                              H      H      CH.sub.2                                                                         4 mp. 117.5° C./ [α].sub.D.sup.20 =                                -62.87°                                                                (c = 1% in CH.sub.3 OH)                                                       (-) - (R) 2 HCl . 1/2H.sub.2 O                        100                                                                              17                                                                              H      H      CH.sub.2                                                                         5 mp. 191.8° C./ [α].sub.D.sup.20 =                                -59.92°                                                                (c = 1% in CH.sub.3 OH)                                                       (-) - (R) 2 HCl . 1/2 H.sub.2 O                       101                                                                              17                                                                              6-F    H      CH.sub.2                                                                         4 mp. 209.5° C./ [α].sub.D.sup.20 =                                -63.68°                                                                (-) - (R) 2 HCl                                       102                                                                              21                                                                              6-CH.sub.2 NH.sub.2                                                                  H      CH.sub.2                                                                         3 mp. 240.1° C./ 3 HCl .  3/2 H.sub.2            __________________________________________________________________________                            O                                                 

                                      TABLE 3                                     __________________________________________________________________________     ##STR61##                                                                     ##STR62##                                                                         ##STR63##                                                                        ##STR64##                                                                          ##STR65##                                                                        ##STR66##                                                                         ##STR67##                                                                                    ##STR68##                                                                                    ##STR69##                   __________________________________________________________________________    103 10 H    H  CH.sub.2                                                                           ##STR70##                                                                                    ##STR71##     mp. 264.2° C./ .2                                                      HCl                          104 10 H    H  CH.sub.2                                                                           ##STR72##                                                                                    ##STR73##     mp. 219.2° C./ .2                                                      HCl                          105 10 H    H  CH.sub.2                                                                           ##STR74##                                                                                    ##STR75##     mp. 121.6° C.         106 10 6-F  H  CH.sub.2                                                                           ##STR76##                                                                                    ##STR77##     mp. 201.0° C./ .2                                                      HCl                          107 10 H    H  CH.sub.2                                                                           ##STR78##                                                                                    ##STR79##     mp. 220.4° C. . 2                                                      HCl.  1/2 H.sub.2 O                                                           trans                        108 10 H    H  CH.sub.2                                                                           ##STR80##                                                                                    ##STR81##     mp. 243.2° C./ .2                                                      HCl cis                      109 10 H    H  CH.sub.2                                                                           ##STR82##                                                                                    ##STR83##     mp. 130.4° C.                                                          H.sub.2 SO.sub.3 (1:1)       110 10 H    H  CH.sub.2                                                                           ##STR84##                                                                                    ##STR85##     mp. 158.5° C.                                                          ethanedioate (1:1)           111 10 H    H  CH.sub.2                                                                           ##STR86##                                                                                    ##STR87##     mp. 121.1° C.                                                          ethanedioate (1:2)           112 10 H    H  CH.sub.2                                                                           ##STR88##                                                                                    ##STR89##     mp. 179.8° C./                                                         ethanedioate (1:2)           113 10 H    H  CH.sub.2                                                                           ##STR90##                                                                                    ##STR91##     mp. 192.5° C.                                                          ethanedioate (1:1)           114 10 H    H  CH.sub.2                                                                           ##STR92##                                                                                    ##STR93##     mp. 127.8° C.         115 10 H    H  CH.sub.2                                                                           ##STR94##                                                                                    ##STR95##     .HCl .  1/2 H.sub.2 O        116 10 7-C.sub.2 H.sub.5                                                                  H  CH.sub.2                                                                           ##STR96##                                                                                    ##STR97##     mp. 219.8° C.                                                          ethanedioate (1:2)           117 11 H    H  CH.sub.2                                                                           ##STR98##                                                                                    ##STR99##     liquid                       118 11 H    H  CH.sub.2                                                                           ##STR100##                                                                                   ##STR101##    mp. 140.1° C./                                                         (-) - (R) [α].sub.D                                                     .sup.20                                                                       = -70.68°                                                              (c = 1% in CH.sub.3 OH)      119 11 H    H  CH.sub.2                                                                           ##STR102##                                                                                   ##STR103##    mp. 150.2° C.                                                          ethanedioate (1:2)           120 12 H    H  CH.sub.2                                                                           ##STR104##                                                                                   ##STR105##    mp. 246.6° C.                                                          ethanedioate (1:1)           121 12 H    H  CH.sub.2                                                                           ##STR106##                                                                                   ##STR107##    mp. 202.5° C./ .                                                       2 HCl                        122 12 H    H  CH.sub.2                                                                           ##STR108##                                                                                   ##STR109##    mp. 120.6° C.                                                          (B)                          123 12 H    H  CH.sub.2                                                                           ##STR110##                                                                                   ##STR111##    mp. 254.9° C./.2                                                       HCl (A)                      124 13 H    H  CH.sub.2                                                                           ##STR112##                                                                                   ##STR113##    mp. 220.2° C.                                                          ethanedioate (1:2)           125 14 H    H  O                                                                                  ##STR114##                                                                                   ##STR115##    mp. 252.4° C.                                                          ethanedioate (1:1)           126 14 H    H  O                                                                                  ##STR116##                                                                                   ##STR117##    mp. 218.1° C./ .2                                                      HCl                          127 14 H    H  O                                                                                  ##STR118##                                                                                   ##STR119##    mp. 205.4° C. .                                                        2HCl .  1/2 H.sub.2 O        128 14 H    H  CH.sub.2                                                                           ##STR120##                                                                                   ##STR121##    mp. 141.9° C.         129 15 H    H  CH.sub.2                                                                           ##STR122##                                                                                   ##STR123##    mp. 226.0° C./. 2                                                      HCl                          130 15 H    H  CH.sub.2                                                                           ##STR124##                                                                                   ##STR125##    mp. 165.8° C. . 2                                                      HCl . H.sub.2 O              131 15 6-F  H  CH.sub.2                                                                           ##STR126##                                                                                   ##STR127##    mp. 242.1° C./                                                         (-) - (R) . 2 HCl                                                             [α].sub.D.sup.20 =                                                      -72.75°                                                                (c = 1% in CH.sub.3 OH)      132 15 H    H  CH.sub.2                                                                           ##STR128##                                                                                   ##STR129##    mp. 254.0° C./ .                                                       2. HCl                       133 15 7-C.sub.2 H.sub.5                                                                  H  CH.sub.2                                                                           ##STR130##                                                                                   ##STR131##    mp. 199.2° C. . 2                                                      HCl .  1/2 H.sub.2 O         134 15 H    H  CH.sub.2                                                                           ##STR132##                                                                                   ##STR133##    mp. 190.6° C./                                                         ethanedioate (1:2)           135 15 H    H  CH.sub.2                                                                           ##STR134##                                                                                   ##STR135##    mp. 190.3° C./                                                         ethanedioate (1:2)           136 16 H    H  CH.sub.2                                                                           ##STR136##                                                                                   ##STR137##    mp. 239.8° C. . 2                                                      HCl . 1/2 H.sub.2 O          137 16 H    H  CH.sub.2                                                                           ##STR138##                                                                                   ##STR139##    mp. >300.0° C. .                                                       2 HCl                        138 16 H    H  CH.sub.2                                                                           ##STR140##                                                                                   ##STR141##    mp. 172.7° C./ .                                                       2 HCl                        139 16 H    H  CH.sub.2                                                                           ##STR142##                                                                                   ##STR143##    mp. 230.0° C.                                                          (decom.) [α].sub.D.                                                     sup.20 = -57.20°                                                       (c = 0.7% in CH.sub.3                                                         OH)                                                                           (-) - (R)                                                                     . 2HCl.  3/2 H.sub.2 O       140 16 H    H  CH.sub.2                                                                           ##STR144##                                                                                   ##STR145##    mp. 175.9° C. . 2                                                      HCl.  1/2 H.sub.2 O                                                           trans                        141 16 H    H  CH.sub.2                                                                           ##STR146##                                                                                   ##STR147##    mp. 196.7° C. . 2                                                      HCl.  1/2 H.sub.2 O cis      142 16 H    H  CH.sub.2                                                                           ##STR148##                                                                                   ##STR149##    mp. 200.4° C. .2                                                       (COOH).sub.2 .  1/2                                                           H.sub.2 O                    143 16 H    H  CH.sub.2                                                                           ##STR150##                                                                                   ##STR151##    mp. 158.2° C.                                                          ethanedioate (1:2)           144 16 H    H  CH.sub.2                                                                           ##STR152##                                                                                   ##STR153##    mp. 281.3° C. .2                                                       HCl trans                    145 16 H    H  CH.sub.2                                                                           ##STR154##                                                                                   ##STR155##    mp. 273.1° C. .2                                                       HCl cis                      146 16 H    H  CH.sub.2                                                                           ##STR156##                                                                                   ##STR157##    mp. 170.0° C. .2                                                       HCl . H.sub.2 O              147 18 5-OH H  CH.sub.2                                                                           ##STR158##                                                                                   ##STR159##    mp. 152.1° C.                                                          ethanedioate (1:2)           148 19 H    H  CH.sub.2                                                                           ##STR160##                                                                                   ##STR161##    mp. 235.1° C. . 2                                                      HCl . NH.sub.4 Cl            149 19 H    H  CH.sub.2                                                                           ##STR162##                                                                                   ##STR163##    mp. 149.9° C./ .                                                       2 HCl                        150 19 H    H  CH.sub.2                                                                           ##STR164##                                                                                   ##STR165##    mp. 97.5° C. . 2                                                       HCl                          151 19 H    H  CH.sub.2                                                                           ##STR166##                                                                                   ##STR167##    mp. 156.4° C./ .                                                       2HCl .                                                                        1/2 (CH.sub.3).sub.2                                                          CHOH                         152 19 7-CH.sub.3                                                                         H  CH.sub.2                                                                           ##STR168##                                                                                   ##STR169##    mp. 224.4° C./ .                                                       2 HCl                        153 19 7-C.sub.2 H.sub.5                                                                  H  CH.sub.2                                                                           ##STR170##                                                                                   ##STR171##    mp. 214.1° C.                                                          ethanedioate (1:2)           154 19 7-C.sub.2 H.sub.5                                                                  H  CH.sub.2                                                                           ##STR172##                                                                                   ##STR173##    mp. 157.8° C. . 2                                                      HCl.  1/2 H.sub.2 O          155 20 6-F  H  CH.sub.2                                                                           ##STR174##                                                                                   ##STR175##    mp. 228.2° C./ .                                                       HCl                          __________________________________________________________________________

                                      TABLE 4                                     __________________________________________________________________________     ##STR176##                                                                    ##STR177##                                                                        ##STR178##                                                                       ##STR179##                                                                                ##STR180##                                                                            ##STR181##                                        __________________________________________________________________________    156 11                                                                                ##STR182##                                                                                ##STR183##                                                                           --                                                 157 11                                                                                ##STR184##                                                                                ##STR185##                                                                           mp. 105.8° C. . 2 HCl .  1/2  H.sub.2                                  O                                                  158 16                                                                                ##STR186##                                                                                ##STR187##                                                                           mp. 242.0° C. . 2 HCl . 2 H.sub.2 O         159 16                                                                                ##STR188##                                                                                ##STR189##                                                                           mp. 229.4° C./ .2 HCl                       160 17                                                                                ##STR190##                                                                                ##STR191##                                                                           liquid/ . 2 HCl . H.sub.2 O                        __________________________________________________________________________

                                      TABLE 5                                     __________________________________________________________________________     ##STR192##                                                                    ##STR193##                                                                       ##STR194##                                                                      ##STR195##                                                                        ##STR196##                                                                       ##STR197##                                                                             ##STR198##                                                                            ##STR199##                                      __________________________________________________________________________    161                                                                              10                                                                              H   H  (CH.sub.2).sub.2                                                                        ##STR200##                                                                           mp. 188.6° C. ethanedioate (1:1)          162                                                                              12                                                                              6-Br                                                                              H  (CH.sub.2).sub.3                                                                        ##STR201##                                                                           mp. 191.7° C. ethanedioate (1:1)          163                                                                              12                                                                              H   H  CH(CH.sub.3)                                                                            ##STR202##                                                                           mp. 183.0° C. (2S) . HCl                  164                                                                              12                                                                              H   H  CH(CH.sub.3)                                                                            ##STR203##                                                                           mp. 182.1° C. (2R) . HCl                  165                                                                              16                                                                              H   H  (CH.sub.2).sub.3                                                                        ##STR204##                                                                           mp. 170.6° C. ethanedioate (1:2)          166                                                                              16                                                                              H   H  (CH.sub.2).sub.2                                                                        ##STR205##                                                                           mp. 193.5° C. ethanedioate (1:2)          167                                                                              16                                                                              H   H  CH(CH.sub.3)                                                                            ##STR206##                                                                           mp. 110.6° C. (2S) . 2 HCl.  1/2                                       H.sub.2 O                                        168                                                                              16                                                                              H   H  CH(CH.sub.3)                                                                            ##STR207##                                                                           mp. 205.5° C. (2R) . 2                    __________________________________________________________________________                                 HCl                                          

C. Pharmacological example EXAMPLE 23

Segments of basilar aeries taken from pigs (anaesthetised with sodiumpentobarbital) were mounted for recording of isometric tension in organbaths. The preparations were bathed in Krebs--Henseleit solution. Thesolution was kept at 37° C. and gassed with a mixture of 95% O₂ -5% CO₂.The Preparations were stretched until a stable basal tension of 2 gramswas obtained.

The preparations were made to constrict with serotonin (3×10⁻⁷ M). Theresponse to the addition of serotonin was measured and subsequently theserotonin was washed away.

This Procedure was repeated until stable responses were obtained.

Subsequently the test compound was administered to the organ bath andthe constriction of the Preparation was measured. This constrictiveresponse is expressed as a Percentage of the response to serotonin asmeasured Previously.

The ED₅₀ -value (molar concentration) is defined as the concentration atwhich a test compound causes 50% of the constrictive response obtainedwith serotonin. Said

ED₅₀ -values are estimated from experiments on three differentpreparations.

In table 6 the ED₅₀ -values of compounds of formula (I) are presented.

                  TABLE 6                                                         ______________________________________                                        Co. No.             ED.sub.50 (M)                                             ______________________________________                                        3                   1.46·10.sup.-7                                   5                   5.15·10.sup.-7                                   13                  4.22·10.sup.-8                                   18                  4.90·10.sup.-8                                   46                  1.00·10.sup.-6                                   48                  3.06·10.sup.-7                                   56                  1.87·10.sup.-7                                   57                  5.42·10.sup.-7                                   62                  3.17·10.sup.-8                                   63                  1.21·10.sup.-7                                   64                  8.97·10.sup.-8                                   65                  2.21·10.sup.-7                                   66                  6.56·10.sup.-7                                   67                  1.77·10.sup.-8                                   68                  3.33·10.sup.-8                                   70                  6.37·10.sup.-9                                   72                  2.34·10.sup.-8                                   73                  3.46·10.sup.-9                                   76                  9.19·10.sup.-9                                   78                  3.54·10.sup.-8                                   82                  1.76·10.sup.-8                                   84                  1.33·10.sup.-8                                   86                  4.16·10.sup.-8                                   87                  8.87·10.sup.-8                                   88                  7.02·10.sup.-9                                   89                  7.94·10.sup.-8                                   95                  8.17·10.sup.-8                                   97                  9.76·10.sup.-8                                   98                  3.42·10.sup.-8                                   99                  4.22·10.sup.-8                                   106                 3.90·10.sup.-8                                   111                 1.67·10.sup.-8                                   113                 1.63·10.sup.-8                                   114                 9.56·10.sup.-8                                   115                 4.51·10.sup.-8                                   116                 6.82·10.sup.-8                                   129                 4.44·10.sup.-7                                   130                 3.36·10.sup.-8                                   133                 5.27·10.sup.-8                                   136                 8.10·10.sup.-7                                   139                 1.50·10.sup.-7                                   148                 4.95·10.sup.-7                                   149                 9.92·10.sup.-8                                   150                 4.69·10.sup.-8                                   151                 2.71·10.sup.-8                                   152                 5.60·10.sup.-8                                   153                 2.18·10.sup.-8                                   ______________________________________                                    

D. Composition Examples

"Active ingredient" (A.I.) as used throughout these examples relates toa compound of formula (I), a pharmaceutically acceptable acid additionsalt or a stereochemically isomeric form thereof.

EXAMPLE 24: Oral Drops

500 Grams of the A.I. was dissolved in 0.5 1 of 2-hydroxypropanoic acidand 1.51 of the Polyethylene glycol at 60°˜80° C. After cooling to30°˜40° C. there were added 351 of polyethylene glycol and the mixturewas stirred well. Then there was added a solution of 1750 grams ofsodium saccharin in 2.51 of purified water and while stirring there wereadded 2.5 1 of cocoa flavor and polyethylene glycol q.s. to a volume of501, providing an oral drop solution comprising 10 mg/ml of A.I. Theresulting solution was filled into suitable containers.

EXAMPLE 25: Oral Solution

9 Grams of methyl 4-hydroxybenzoate and 1 gram of propyl4-hydroxybenzoate were dissolved in 41 of boiling purified water. In 31of this solution were dissolved first 10 grams of2,3-dihydroxybutanedioic acid and thereafter 20 grams of the A.I. Thelatter solution was combined with the remaining part of the formersolution and 121 1,2,3-propanetriol and 31 of sorbitol 70% solution wereadded thereto. 40 Grams of sodium saccharin were dissolved in 0.51 ofwater and 2 ml of raspberry and 2 ml of gooseberry essence were added.The latter solution was combined with the former, water was added q.s.to a volume of 201 providing an oral solution comprising 5 mg of theactive ingredient per teaspoonful (5 ml). The resulting solution wasfilled in suitable containers.

EXAMPLE 26: Capsules

20 Grams of the A.I., 6 grams sodium lauryl sulfate, 56 grams starch, 56grams lactose, 0.8 grams colloidal silicon dioxide, and 1.2 gramsmagnesium stearate were vigorously stirred together. The resultingmixture was subsequently filled into 1000 suitable hardened gelatincapsules, comprising each 20 mg of the active ingredient.

EXAMPLE 27: Film-Coated Tablets

Preparation of tablet core

A mixture of 100 grams of the A.I., 570 grams lactose and 200 gramsstarch was mixed well and thereafter humidified with a solution of 5grams sodium dodecyl sulfate and 10 grams polyvinylpyrrolidone in about200 ml of water. The wet powder mixture was sieved, dried and sievedagain. Then there was added 100 grams microcrystalline cellulose and 15grams hydrogenated vegetable oil. The whole was mixed well andcompressed into tablets, giving 10.000 tablets, each containing 10 mg ofthe active ingredient.

Coating

To a solution of 10 grams methyl cellulose in 75 ml of denaturatedethanol there was added a solution of 5 grams of ethyl cellulose in 150ml of dichloromethane. Then there were added 75 ml of dichloromethaneand 2.5 ml 1,2,3-propanetriol. 10 Grams of polyethylene glycol wasmolten and dissolved in 75 ml of dichloromethane. The latter solutionwas added to the former and then there were added 2.5 grams of magnesiumoctadecanoate, 5 grams of polyvinylpyrrolidone and 30 ml of concentratedcolour suspension and the whole was homogenated. The tablet cores werecoated with the thus obtained mixture in a coating apparatus.

EXAMPLE 28: Injectable Solution

1.8 Grams methyl 4-hydroxybenzoate and 0.2 grams propyl4-hydroxybenzoate were dissolved in about 0.51 of boiling water forinjection. After cooling to about 50° C. there were added while stirring4 grams lactic acid, 0.05 grams propylene glycol and 4 grams of the A.I.The solution was cooled to room temperature and supplemented with waterfor injection q.s. ad 11, giving a solution comprising 4 mg/ml of A.I.The solution was sterilized by filtration (U.S.P. XVII p. 811) andfilled in sterile containers.

EXAMPLE 29: Suppositories

3 Grams A.I. was dissolved in a solution of 3 grams2,3-dihydroxybutanedioic acid in 25 ml polyethylene glycol 400.12 Gramssurfactant (SPAN®) and triglycerides (Witepsol 555®) q.s. ad 300 gramswere molten together. The latter mixture was mixed well with the formersolution. The thus obtained mixture was poured into moulds at atemperature of 37°-38° C. to form 100 suppositories each containing 30mg/ml of the A.I.

EXAMPLE 30: Injectable Solution

60 Grams of A.I. and 12 grams of benzylalcohol were mixed well andsesame oil was added q.s. ad 11, giving a solution comprising 60 mg/mlof A.I. The solution was sterilized and filled in sterile containers.

We claim:
 1. A compound having the formula: ##STR208## apharmaceutically acceptable acid addition salt thereof, or astereochemically isomeric form thereof, wherein:X is O, CH₂ or a directbond; R¹ is hydrogen or C₁₋₆ alkyl; R² is hydrogen, C₁₋₆ alkyl, C₃₋₆alkenyl or C₃₋₆ alkynyl; R³ is hydrogen or C₁₋₆ alkyl; R⁴ is hydrogen ofC₁₋₆ alkyl Alk¹ is a bivalent C₁₋₃ alkanediyl radical; A is a bivalentradical of the formula: ##STR209## wherein: R⁵ and R⁶ individually arehydrogen or C₁₋₄ alkyl and p is 0, 1 or 2; and R⁷ and R⁸ eachindependently are hydrogen, halo, C₁₋₆ alkyl, C₃₋₆ alkenyl, C₃₋₆alkynyl, hydroxy, C₁₋₆ alkyloxy, cyano, aminoC₁₋₆ alkyl, carboxyl, C₁₋₆alkyloxycarbonyl, nitro, amino, aminocarbonyl, C₁₋₆ alkylcarbonylamino,or mono- or di(C₁₋₆ alkyl)amino.
 2. A compound according to claim 1,wherein Alk¹ is CH₂.
 3. A compound according to claim 1, wherein X isCH₂ and wherein R⁷ and R⁸ each independently are hydrogen, halo, C₁₋₆alkyl, C₁₋₆ alkyloxy, hydroxy, cyano, nitro, aminoC₁₋₆ alkyl, amino,C₁₋₆ alkylcarbonylamino.
 4. A compound according to claim 2 wherein R⁶is hydrogen.
 5. A compound according to claim 3 wherein R⁶ is hydrogen.6. A compound according to claim 4 wherein R⁵ is hydrogen.
 7. A compoundaccording to claim 5 wherein R⁵ is hydrogen.
 8. A composition comprisinga pharmaceutically acceptable carrier and as an active ingredient aneffective vasoconstricting amount of a compound as defined in claim 1.9. A composition comprising a pharmaceutically acceptable carrier and asan active ingredient an effective vasoconstricting amount of a compoundas defined in claim
 2. 10. A composition comprising a pharmaceuticallyacceptable carrier and as an active ingredient an effectivevasoconstricting amount of a compound as defined in claim
 3. 11. Acomposition comprising a pharmaceutically acceptable carrier and as anactive ingredient an effective vasoconstricting amount of a compound asdefined in claim
 4. 12. A composition comprising a pharmaceuticallyacceptable carrier and as an active ingredient an effectivevasoconstricting amount of a compound as defined in claim
 5. 13. Acomposition comprising a pharmaceutically acceptable carrier and as anactive ingredient an effective vasoconstricting amount of a compound asdefined in claim
 6. 14. A composition comprising a pharmaceuticallyacceptable carrier and as an active ingredient an effectivevasoconstricting amount of a compound as defined in claim
 7. 15. Amethod of treating migraine, which method comprises administering topatients in need of such treatment a therapeutically effective amount ofa compound as defined in claim 1.